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1. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author: Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: AcademicSubjects/SCI01140, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, DISEASE, Pathogenesis, Cohort Studies, 0302 clinical medicine, cytokine, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Association Studies Article, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, ARCHITECTURE, CHRONIC INFLAMMATION, 1184 Genetics, developmental biology, physiology, General Medicine, RECEPTOR IL-6R GENE, C-REACTIVE PROTEIN, hla-drb1 gene, 3. Good health, Medical genetics, Medical Genetics, chromosomes, medicine.medical_specialty, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, anti-inflammatory agents, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Interleukin 6, Molecular Biology, Medicinsk genetik, 030304 developmental biology, PRODUCE IL-6, Interleukin-6, Chromosome, Receptors, Interleukin-6, RHEUMATOID-ARTHRITIS, Interleukin 1 Receptor Antagonist Protein, Gene Expression Regulation, Genetic Loci, CELLS, biology.protein, 1182 Biochemistry, cell and molecular biology, Human genome, 3111 Biomedicine, Genome-Wide Association Study, HLA-DRB1 Chains, Interleukin-1
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Published: 2021
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2. Identifying the Common Genetic Basis of Antidepressant Response

Author: Sara A. Paciga, Richard M. Weinshilboum, Andrew M. McIntosh, Tim B. Bigdeli, Stephanie H. Witt, Sven Cichon, Glyn Lewis, Henning Teismann, Brenda W.J.H. Penninx, Gerome Breen, Roseann E. Peterson, Saira Saeed Mirza, Diego Albani, Lisa Jones, Andreas J. Forstner, Sara Mostafavi, Julien Bryois, Qingqin S. Li, Kenneth S. Kendler, Thomas Damm Als, Fernando S. Goes, Marie Bækvad-Hansen, Nancy L. Pedersen, Gianluigi Forloni, Per Qvist, Carsten Horn, Per Hoffmann, Steven P. Hamilton, Georg Homuth, Michael Gill, Julien Mendlewicz, Katharina Domschke, Volker Arolt, Adrian I. Campos, Christine Søholm Hansen, Scott D. Gordon, Hogni Oskarsson, Peter McGuffin, Oliver Pain, Eric Jorgenson, Victoria S. Marshe, Stacy Steinberg, Bertram Müller-Myhsok, Mark Adams, J. Raymond DePaulo, Rick Jansen, Katherine J. Aitchison, Vassily Trubetskoy, Henry Völzke, Manuel Mattheisen, Bernard Ng, James A. Knowles, Dorret I. Boomsma, Tracy Air, Elisabeth B. Binder, Ian B. Hickie, Christel M. Middeldorp, Tõnu Esko, David M. Hougaard, E.J.C. de Geus, Toni-Kim Clarke, Helena Gaspar, Bernhard T. Baune, Abdel Abdellaoui, Engilbert Sigurdsson, Andres Metspalu, Klaus Berger, Jorge A. Quiroz, Patrick F. Sullivan, Aartjan T.F. Beekman, Thomas Hansen, Panagiotis Ferentinos, Jürgen Wellmann, Miguel E. Rentería, Daniel Umbricht, Marcella Rietschel, Stanley I. Shyn, Chiara Fabbri, Hreinn Stefansson, Jerome C. Foo, Daniel Souery, Zoltán Kutalik, Yu-Li Liu, Paul F. O'Reilly, Michael John Owen, Nese Direk, Douglas F. Levinson, Stuart Montgomery, Hamdi Mbarek, David M. Howard, Guido Bondolfi, Lucía Colodro-Conde, Pippa A. Thomson, Merete Nordentoft, Stefan Kloiber, Yunpeng Wang, Michael Conlon O'Donovan, Grant C.B. Sinnamon, Alexander Viktorin, Hilary K. Finucane, Esben Agerbo, Stefan Herms, Markus M. Nöthen, Till F. M. Andlauer, Divya Mehta, Bradley T. Webb, Joanna M. Biernacka, David J. Porteous, Jordan W. Smoller, Jonathan R. I. Coleman, Dean F. MacKinnon, Farnush Farhadi Hassan Kiadeh, Baptiste Couvy-Duchesne, Evelin Mihailov, Eleanor M. Wigmore, Franziska Degenhardt, Jianxin Shi, Dale R. Nyholt, Enda M. Byrne, Stephan Ripke, Ole Mors, Patrik K. E. Magnusson, Eric J. Lenze, Warren W. Kretzschmar, Masaki Kato, Marcus Ising, Ian Jones, Lynsey S. Hall, Wouter J. Peyrot, Ling Shen, Nader Perroud, Na Cai, Maciej Trzaskowski, Matthias Nauck, Isaac S. Kohane, Enrico Domenici, Fabian Streit, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Enrique Castelao, Margarita Rivera, Mojca Z. Dernovsek, John P. Rice, Joseph Zohar, Gail Davies, Andrew C. Heath, Josef Frank, Wesley K. Thompson, Caroline Hayward, Penelope A. Lind, Thorgeir E. Thorgeirsson, Rudolf Uher, Jana Strohmaier, Henriette N. Buttenschøn, Erin C. Dunn, Jonas Bybjerg-Grauholm, Alexander Teumer, Jakob Grove, Eske M. Derks, Nicholas G. Martin, Jodie N. Painter, Myrna M. Weissman, Preben Bo Mortensen, Michel G. Nivard, Catherine Schaefer, Yihan Li, Daniel J. Smith, Shih-Jen Tsai, Niamh Mullins, Jian Yang, Marianne Giørtz Pedersen, Dan Rujescu, Thomas G. Schulze, Lili Milani, Yuri Milaneschi, Giorgio Pistis, James B. Potash, Neven Henigsberg, Nicholas John Craddock, Karen Hodgson, Silviu-Alin Bacanu, Shantel Weinsheimer, Charles F. Reynolds, Johannes H. Smit, Gonneke Willemsen, Futao Zhang, Henning Tiemeier, Grant W. Montgomery, Martin Preisig, Udo Dannlowski, Thalia C. Eley, Thomas Werge, Katherine E. Tansey, Jane H. Christensen, Julia Kraft, Ian J. Deary, Cathryn M. Lewis, Sarah E. Medland, André G. Uitterlinden, Daniel J. Müller, Carsten Bøcker Pedersen, Gustavo Turecki, Hans J. Grabe, Matthew Traylor, Brien P. Riley, Roy H. Perlis, Patrick J. McGrath, Conor V. Dolan, Hualin S. Xi, Jonathan Marchini, Robert A. Schoevers, Albert M. van Hemert, Anders D. Børglum, Susanne Lucae, Jouke-Jan Hottenga, Kari Stefansson, Benoit H. Mulsant, Francis M. Mondimore, Naomi R. Wray, Yang Wu, Wolfgang Maier, Danielle Posthuma, Annamaria Cattaneo, Gregory E. Crawford, Siegfried Kasper, Alessandro Serretti, Tania Carrillo-Roa, Robert Maier, Pamela A. F. Madden, Eva C. Schulte, Jens Treutlein, Joanna Hauser, Sandra Van der Auwera, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Methodology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Adult Psychiatry, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Epidemiology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine
Subjects: Oncology, MDD, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, Biology, Antidepressant response, Depression, GWAS, Genetics, Polygenic score, SDG 3 - Good Health and Well-being, Internal medicine, Genetic variation, medicine, ddc:610, Genetic association, General Medicine, Heritability, medicine.disease, Schizophrenia, Sample size determination, Settore BIO/14 - Farmacologia, Major depressive disorder
Abstract: Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.
Published: 2022
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3. Substance use: Interplay between polygenic risk and neighborhood environment

Author: Dorret I. Boomsma, Gonneke Willemsen, Jouke-Jan Hottenga, Karin J. H. Verweij, Joëlle A. Pasman, Jacqueline M. Vink, Iryna O. Fedko, Abdel Abdellaoui, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, and Adult Psychiatry
Subjects: Adult, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Gene-environment correlation, Substance-Related Disorders, Twins, Poison control, Genome-wide association study, Substance use, Toxicology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Residence Characteristics, Risk Factors, Medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Gene–environment interaction, Socioeconomic status, Netherlands, Pharmacology, biology, business.industry, Neighborhood, Human factors and ergonomics, Middle Aged, biology.organism_classification, Gene-environment interaction, Polygenic scores, Psychiatry and Mental health, Cross-Sectional Studies, Social Class, Cohort, Female, Cannabis, business, Developmental Psychopathology, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract: Contains fulltext : 216912.pdf (Publisher’s version ) (Open Access) Background: Tobacco, alcohol, and cannabis use are prevalent behaviors that pose considerable health risks. Genetic vulnerability and characteristics of the neighborhood of residence form important risk factors for substance use. Possibly, these factors do not act in isolation. This study tested the interaction between neighborhood characteristics and genetic risk (gene-environment interaction, GxE) and the association between these classes of risk factors (gene-environment correlation, rGE) in substance use. Methods: Two polygenic scores (PGS) each (based on different discovery datasets) were created for smoking initiation, cigarettes per day, and glasses of alcohol per week based on summary statistics of different genome-wide association studies (GWAS). For cannabis initiation one PGS was created. These PGS were used to predict their respective phenotype in a large population-based sample from the Netherlands Twin Register (N = 6,567). Neighborhood characteristics as retrieved from governmental registration systems were factor analyzed and resulting measures of socioeconomic status (SES) and metropolitanism were used as predictors. Results: There were (small) main effects of neighborhood characteristics and PGS on substance use. One of the 14 tested GxE effects was significant, such that the PGS was more strongly associated with alcohol use in individuals with high SES. This was effect was only significant for one out of two PGS. There were weak indications of rGE, mainly with age and cohort covariates. Conclusion: We conclude that both genetic and neighborhood-level factors are predictors for substance use. More research is needed to establish the robustness of the findings on the interplay between these factors. 8 p.
Published: 2020
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4. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
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5. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS interaction (rs7302529,p=1.6×10−7; rs73033497,p=8.8×10−7; rs7914279,p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

6. Identical twins carry a persistent epigenetic signature of early genome programming

Author: Jordana T. Bell, Claudio D. Stern, Scott D. Gordon, Erik A. Ehli, Silvère M. van der Maarel, Jonathan Mill, Gibran Hemani, Hamdi Mbarek, Juan E. Castillo-Fernandez, Tim D. Spector, Allan F. McRae, Catharina E. M. van Beijsterveldt, Jouke-Jan Hottenga, Veronika V. Odintsova, Nicholas G. Martin, Jaakko Kaprio, Eilis Hannon, P. Eline Slagboom, Gonneke Willemsen, Bastiaan T. Heijmans, Sara N. Lundgren, Josine L. Min, Jenny van Dongen, Miina Ollikainen, Dorret I. Boomsma, Pei-Chien Tsai, Karen Sugden, Charles E. Breeze, Terrie E. Moffitt, Bruno Reversade, Lucia Daxinger, Franziska Paul, Fiona A. Hagenbeek, Eco J. C. de Geus, Grant W. Montgomery, T.D. Spector, Avshalom Caspi, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development, Reversade, Bruno, van Dongen, Jenny, Gordon, Scott D., McRae, Allan F., Odintsova, Veronika V., Mbarek, Hamdi, Breeze, Charles E., Sugden, Karen, Lundgren, Sara, Castillo-Fernandez, Juan E., Hannon, Eilis, Moffitt, Terrie E., Hagenbeek, Fiona A., van Beijsterveldt, Catharina E. M., Hottenga, Jouke Jan, Tsai, Pei-Chien, Min, Josine L., Hemani, Gibran, Ehli, Erik A., Paul, Franziska, Stern, Claudio D., Heijmans, Bastiaan T., Slagboom, P. Eline, Daxinger, Lucia, van der Maarel, Silvere M., de Geus, E. J. C., Willemsen, Gonneke, Montgomery, Grant W., Ollikainen, Miina, Kaprio, Jaakko, Spector, Tim D., Bell, Jordana T., Mill, Jonathan, Caspi, Avshalom, Martin, Nicholas G., Boomsma, Dorret, I., School of Medicine, APH - Personalized Medicine, APH - Mental Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Breeze, Charles, Martin, Nicholas, Boomsma, Dorret, Institute for Molecular Medicine Finland, and Epigenetics of Complex Diseases and Traits
Subjects: Epigenomics, Somatic cell, General Physics and Astronomy, Monozygotic twin, PROBE DESIGN BIAS, Genome, Epigenesis, Genetic, NORMALIZATION, 0302 clinical medicine, Genetics research, Registries, Probe design bias, DNA methylation, Vanishing twin, Register, Cells, Normalization, Association, Ontology, Mothers, Family, 112 Statistics and probability, Science and technology, Finland, Netherlands, 0303 health sciences, Multidisciplinary, Zygote, Twinning, Monozygotic, MOTHERS, 1184 Genetics, developmental biology, physiology, VANISHING TWIN, ASSOCIATION, Middle Aged, 3142 Public health care science, environmental and occupational health, FAMILY, Multidisciplinary sciences, Embryogenesis, Adult, Genotype, Heterochromatin, Science, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Centromere, Humans, Epigenetics, Genetic epigenesis, REGISTER, Retrospective Studies, 030304 developmental biology, 3112 Neurosciences, Twins, Monozygotic, General Chemistry, United Kingdom, 3141 Health care science, ONTOLOGY, Evolutionary biology, CELLS, 030217 neurology & neurosurgery
Abstract: The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues. Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin., Netherlands Organization for Scientific Research (NWO); Biobanking and Biomolecular Research Infrastructure (BBMRI–NL); NWO Large Scale infrastructures; X-Omics
Published: 2021
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7. DNA methylation in peripheral tissues and Left-handedness

Author: Veronika Odintsova, Matthew Sudermann, Fiona Hagenbeek, Doretta Caramaschi, Jouke-Jan Hottenga, Rene Pool, Biobank-based Integrative Omics Study Consortium BIOS, Conor Dolan, Lannie Ligthart, Catharina van Beijsterveldt, Gonneke Willemsen, Eco de Geus, Jeffrey Beck, Erik Ehli, Gabriel Cuellar-Partida, David Evans, Sarah Medland, Caroline Relton, Dorret Boomsma, and Jenny van Dongen
Subjects: Pathology, medicine.medical_specialty, DNA methylation, medicine, Biology, Left handedness, Peripheral
Abstract: Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study (EWAS) of left-handedness. In a meta-analysis of 3,914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. We identified differentially methylated regions at 20q11.23 (P = 0.00004) and 2p25.1 (P = 0.03), which were less methylated in left-handed adults. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1,737), we observed moderately stable associations across age (correlation range [0.355–0.578]) but inconsistent across tissues (correlation range [-0.384-0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.
Published: 2021
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8. Genetic Meta-Analysis of Twin Birth Weight Shows High Genetic Correlation with Singleton Birth Weight

Author: Anu Loukola, Jeffrey J. Beck, J. Kittelsrud, Conor V. Dolan, Nicholas G. Martin, Kauko Heikkilä, Jouke-Jan Hottenga, Teemu Palviainen, Hamdi Mbarek, Kaare Christensen, Michel G. Nivard, Miina Ollikainen, Gonneke Willemsen, Robert Plomin, Scott D. Gordon, Lu Yi, Matthijs D. van der Zee, Toos C. E. M. van Beijsterveldt, Bart M. L. Baselmans, Sebastian Lundström, Marianne Nygaard, Lene Christiansen, Eva Krapohl, Catarina Almqvist, Meike Bartels, Xu Chen, Patrik K. E. Magnusson, Casey T. Finnicum, Dorret I. Boomsma, Eco J. C. de Geus, Birgit Debrabant, Margot P van de Weijer, Erik A. Ehli, René Pool, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUSLAB, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, and APH - Methodology
Subjects: AcademicSubjects/SCI01140, Adult, LD SCORE REGRESSION, Birth weight, Twins, Gestational Age, BLOOD-PRESSURE, Genome-wide association study, PERINATAL-MORTALITY, HEART-DISEASE, Biology, Genetic correlation, DEVELOPMENTAL ORIGINS, Fetal Development, 03 medical and health sciences, SDG 3 - Good Health and Well-being, CARDIOVASCULAR RISK-FACTORS, Genetics, Birth Weight, Humans, GENOME-WIDE ASSOCIATION, Association Studies Article, Molecular Biology, Genetics (clinical), REGISTER, 030304 developmental biology, 0303 health sciences, Singleton, 030305 genetics & heredity, Infant, Newborn, 1184 Genetics, developmental biology, physiology, General Medicine, Anthropometry, Confidence interval, Genetic architecture, 3. Good health, Sample size determination, Pregnancy, Twin, ADOLESCENT TWIN, 3111 Biomedicine, FETAL ORIGINS, Genome-Wide Association Study, Demography
Abstract: Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardio-metabolic disorders, autoimmune diseases, and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers. Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.
Published: 2021
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9. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021
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10. Cohabitation is associated with a greater resemblance in gut microbiota which can impact cardiometabolic and inflammatory risk

Author: Christel M. Davis, Erik A. Ehli, Dorret I. Boomsma, Gareth E. Davies, Casey T. Finnicum, Jeffrey J. Beck, Gonneke Willemsen, Conor V. Dolan, Eco J. C. de Geus, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, and APH - Personalized Medicine
Subjects: Microbiology (medical), Adult, Male, Netherlands Twin Register (NTR), Intraclass correlation, lcsh:QR1-502, Cohabitation, Gut microbiota, Twin genetics, Biology, Gut flora, Microbiology, behavioral disciplines and activities, lcsh:Microbiology, Genetic profile, Correlation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Humans, Spouses, Phylogeny, 030304 developmental biology, Aged, Netherlands, Genetics, Inflammation, 0303 health sciences, Bacteria, Significant difference, Sequence Analysis, DNA, Twins, Monozygotic, social sciences, Middle Aged, biology.organism_classification, Gastrointestinal Microbiome, Spouse, Cardiovascular Diseases, Female, 030217 neurology & neurosurgery, Biomarkers, Research Article
Abstract: Background The gut microbiota composition is known to be influenced by a myriad of factors including the host genetic profile and a number of environmental influences. Here, we focus on the environmental influence of cohabitation on the gut microbiota as well as whether these environmentally influenced microorganisms are associated with cardiometabolic and inflammatory burden. We perform this by investigating the gut microbiota composition of various groups of related individuals including cohabitating monozygotic (MZ) twin pairs, non-cohabitating MZ twin pairs and spouse pairs. Results A stronger correlation between alpha diversity was found in cohabitating MZ twins (45 pairs, r = 0.64, p = 2.21 × 10− 06) than in non-cohabitating MZ twin pairs (121 pairs, r = 0.42, p = 1.35 × 10− 06). Although the correlation of alpha diversity did not attain significance between spouse pairs (42 pairs, r = 0.23, p = 0.15), the correlation was still higher than those in the 209 unrelated pairs (r = − 0.015, p = 0.832). Bray-Curtis (BC) dissimilarity metrics showed cohabitating MZ twin pairs had the most similar gut microbiota communities which were more similar than the BC values of non-cohabitating MZ twins (empirical p-value = 0.0103), cohabitating spouses (empirical p-value = 0.0194), and pairs of unrelated non-cohabitating individuals (empirical p-valuep-value Conclusions Through the comparison of the microbiota contents of MZ twins with varying cohabitation status and spousal pairs, we showed evidence of environmentally influenced OTUs, one of which had a significant association with cardiometabolic and inflammatory burden scores.
Published: 2019
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11. Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness

Author: Abraham A. Palmer, Dorret I. Boomsma, Sandra Sanchez-Roige, Jouke-Jan Hottenga, Alexander Neumann, Stephanie Cacioppo, Damiaan Denys, Gonneke Willemsen, Jorien L. Treur, Abdel Abdellaoui, Najaf Amin, Michel G. Nivard, Miriam A. Mosing, John T. Cacioppo, Julia Sealock, Bart M. L. Baselmans, Hill F. Ip, Karin J. H. Verweij, I. Szilagyi, Jessica Dennis, Sarah L. Elson, Henning Tiemeier, Matthijs D. van der Zee, Yi Lu, Cornelia M. van Duijn, Pierre Fontanillas, Lea K. Davis, Nancy L. Pedersen, Epidemiology, Psychiatry, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, APH - Mental Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Social Psychology, and APH - Methodology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Male, Multifactorial Inheritance, Genotype, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Mendelian randomization, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Phenomics, Association Studies Article, Molecular Biology, Genetics (clinical), Loneliness, Mental Disorders, Mendelian Randomization Analysis, General Medicine, Mental health, Genetic architecture, 3. Good health, 030104 developmental biology, Mental Health, Phenotype, Health, Marital status, Female, medicine.symptom, 030217 neurology & neurosurgery, Clinical psychology, Genome-Wide Association Study
Abstract: Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.
Published: 2019
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12. Epigenome-wide association study of left-handedness for different tissues and ages

Author: Jouke-Jan Hottenga, Veronika V. Odintsova, Jenny van Dongen, Erik A. Ehli, Doretta Caramaschi, Fiona A. Hagenbeek, Jeffrey J. Beck, Gonneke Willemsen, René Pool, Dorret I. Boomsma, Catharina E. M. van Beijsterveldt, David M. Evans, Caroline L Relton, Eco J. C. de Geus, Gabriel Cuellar-Partida, Lannie Ligthart, Conor V. Dolan, Sarah E. Medland, and Matthew Sudermann
Subjects: Evolutionary biology, Epigenome, Biology, Association (psychology), Left handedness
Abstract: We report the first epigenome-wide association study of left-handedness, a trait with low heritability for which epigenetic mechanisms have been proposed as an underlying etiological mechanism. A region-based meta-analysis of whole blood genome-wide DNA methylation data from two cohorts (3,914 adults) identified differentially methylated regions annotated to BLCAP (20q11.23), a negative regulator of cell growth involved in apoptosis, NNAT (20q11.23), involved in brain development, and IAH1 (2p25.1), which encodes an acyl esterase. CpGs located in proximity to the SNPs from the largest GWAS of handedness were more strongly associated with left-handedness than other differentially methylated positions. In longitudinal whole blood samples, cord blood, and buccal cells from children (N = 1,967), the association with handedness displayed moderate stability across age, but little consistency across cell types. These findings suggest new candidate loci associated with handedness.
Published: 2021
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13. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021
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14. Genetic insights into the biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger
Subjects: media_common.quotation_subject, Genetic predisposition, Longevity, Fertility, Disease, Biology, Premature ovarian insufficiency, Bioinformatics, Ovarian reserve, FMR1, Human genetics, media_common
Abstract: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021
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15. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract: The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.
Published: 2021
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16. Large-scale association analyses identify host factors influencing human gut microbiome composition

Author: Jordana T. Bell, Sara Vieira-Silva, Torben Hansen, Andrew D. Paterson, Nicholas J. Timpson, Robert C. Kaplan, Vincent W. V. Jaddoe, Fabian Frost, Gwen Falony, Zachary D. Wallen, Mauro D'Amato, David A. Hughes, Jakob Stokholm, Lude Franke, Matthew A. Jackson, Marc Jan Bonder, Gonneke Willemsen, Dmitrii Borisevich, Hocheol Shin, Kyoko Watanabe, Annique Claringbould, Joanna Szopinska-Tokov, Markus M. Lerch, Caroline I. Le Roy, Markku Laakso, Eran Segal, Daisy Jonkers, Jee-Young Moon, Williams Turpin, Susanna Walter, Xingrong Liu, Lars Agréus, Tim D. Spector, Malte C. Rühlemann, Raul Y. Tito, Daniel Keszthelyi, Gareth E. Davies, Shiraz A. Shah, Ad A.M. Masclee, Carolina Medina-Gomez, Kreete Lüll, Robert D. Burk, Elin Org, Matthias Laudes, Cornelia M. van Duijn, Myriam Fornage, Urmo Võsa, Oluf Pedersen, Lenore J. Launer, Kaitlin H Wade, Juan Antonio Raygoza Garay, Rob Knight, Elad Barkan, Daria V. Zhernakova, Michael Boehnke, Frank Ulrich Weiss, Andre Franke, Jonathan Thorsen, Henry Völzke, Jingyuan Fu, Fernando Rivadeneira, Daphna Rothschild, Robert Kraaij, Katie A. Meyer, Ayse Demirkan, Claire J. Steves, Stefan Weiss, Cisca Wijmenga, Hans Bisgaard, Qi Qibin, Corinna Bang, Rodrigo Bacigalupe, Haydeh Payami, Han-Na Kim, Liesbeth Duijts, Alexander Kurilshikov, Serena Sanna, Kenneth Croitoru, Jeroen Raes, Djawad Radjabzadeh, Eco J. C. de Geus, Jun Wang, Richard G. IJzerman, Harm-Jan Westra, Uwe Völker, Torben Jørgensen, Dorret I. Boomsma, Omer Weissbrod, Alexandra Zhernakova, Alejandro Arias Vasquez, Casey T. Finnicum, Hyung Lae Kim, Marie Joossens, Tue H. Hansen, Henriette A. Moll, Anna Andreasson, Larbi Bedrani, Zlatan Mujagic, Adriaan van der Graaf, Søren J. Sørensen, Aldons J. Lusis, Wolfgang Lieb, Georg Homuth, André G. Uitterlinden, Biological Psychology, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Health Behaviors & Chronic Diseases, Interne Geneeskunde, RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Maag Darm Lever (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Internal Medicine, Epidemiology, Pediatrics, Erasmus MC other, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Translational Immunology Groningen (TRIGR), Internal medicine, ACS - Diabetes & metabolism, and Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Linkage disequilibrium, Genome-wide association study, Genome-wide association studies, Medical and Health Sciences, Oral and gastrointestinal, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, RNA, Ribosomal, 16S, 2.1 Biological and endogenous factors, Aetiology, Child, Lactase, Genetics & Heredity, 2. Zero hunger, Genetics, 0303 health sciences, Biological Sciences, Child, Preschool, MENDELIAN RANDOMIZATION, Female, Life Sciences & Biomedicine, Biotechnology, Adult, 16S, Adolescent, Quantitative Trait Loci, Locus (genetics), Biology, Quantitative trait locus, GENOTYPE IMPUTATION, Microbiology, metagenome, Article, diseases, 03 medical and health sciences, Clinical Research, Genetic variation, Mendelian randomization, Humans, Microbiome, Preschool, Nutrition, 030304 developmental biology, Ribosomal, ecosystem, ENVIRONMENT, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, Human Genome, Genetic Variation, Mendelian Randomization Analysis, FRAMEWORK, Gastrointestinal Microbiome, Metabolism, Metagenomics, genome-wide association, RNA, Bifidobacterium, Digestive Diseases, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P
Published: 2021
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17. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author: Inês Barroso, Gail Davies, H.-Erich Wichmann, Bjarke Feenstra, Peter Vollenweider, Nicholas J. Timpson, Alan F. Wright, Frank Geller, Gérard Waeber, John M. Starr, Benjamin M. Neale, George Davey Smith, Tõnu Esko, Ruth J. F. Loos, Andrew A. Hicks, Pedro Marques-Vidal, Dorret I. Boomsma, Harry Campbell, Zoltán Kutalik, David M. Evans, Scott D. Gordon, Eva Albrecht, Peter P. Pramstaller, Leena Peltonen, Jing Hua Zhao, Lavinia Paternoster, Thomas Hansen, Massimo Mangino, Fazil Aliev, Beate St Pourcain, Panos Deloukas, Heather A. Boyd, Guillaume Paré, Marco P. Boks, Monique M.B. Breteler, Jouke-Jan Hottenga, Xin Li, Kari Stefansson, Ian J. Deary, Jari Lahti, Inga Prokopenko, Nicholas Eriksson, Lili Milani, Nicholas J. Wareham, Jordan W. Smoller, Norman Klopp, Lynn Cherkas, Reedik Mägi, Margaret J. Wright, Peter Kraft, Jacques S. Beckmann, Brenda W.J.H. Penninx, Gabriel Cuellar-Partida, André G. Uitterlinden, Fernando Rivadeneira, Wendy L. McArdle, Johan G. Eriksson, Jiali Han, Jennifer E. Huffman, Andres Metspalu, J.M. Vink, Frank J. A. van Rooij, Christian Gieger, M. Arfan Ikram, Cecilia M. Lindgren, Aarno Palotie, Daniel I. Chasman, Joyce Y. Tung, Liang-Dar Hwang, David A. Hinds, Elisabeth Widen, Caroline Hayward, Michelle Luciano, Johannes H. Smit, Gonneke Willemsen, Dale R. Nyholt, Carolina Medina-Gomez, Nicole M. Warrington, Teemu Palviainen, Stacy Steinberg, Kay-Tee Khaw, Kevin S. O’Connell, Bettina Konte, Gudmar Thorleifsson, Eco J. C. de Geus, John P. Kemp, Mads Melbye, Mark I. McCarthy, Sarah E. Medland, Jaakko Kaprio, Cameron D. Palmer, Joel N. Hirschhorn, Ina Giegling, Scott Melville, Thomas Werge, Nicole Soranzo, Sigurdur H. Magnusson, Maris Teder-Laving, Hreinn Stefansson, Kauko Heikkilä, Cornelia M. van Duijn, David L. Duffy, Samuli Ripatti, Igor Rudan, Annette M. Hartmann, Ole A. Andreassen, Mari Nelis, Ozren Polasek, Vincent Mooser, Mousheng Xu, Eero Vuoksimaa, Katri Räikkönen, Nicholas G. Martin, Dan Rujescu, Tim D. Spector, Dawn M. Waterworth, Danielle M. Dick, Roel A. Ophoff, Epidemiology, Internal Medicine, Psychiatry, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Epidemiology and Data Science, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Pediatric surgery, and APH - Digital Health
Subjects: Male, Netherlands Twin Register (NTR), Linkage disequilibrium, Genome-wide association study, LANGUAGE DOMINANCE, Functional Laterality, Linkage Disequilibrium, Behavioral Neuroscience, 0302 clinical medicine, ddc:150, Gene Frequency, SCHIZOPHRENIA, Genetics, 0303 health sciences, Middle Aged, genetics [Genetic Variation], genetics [Functional Laterality], Schizophrenia, ASYMMETRY, genetics [Polymorphism, Single Nucleotide], Female, Adult, Social Psychology, LATERALIZATION, Experimental and Cognitive Psychology, genetics [Genetic Loci], Biology, Quantitative trait locus, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, LINKAGE ANALYSIS, METAANALYSIS, MICROTUBULE, AUTISM, ORIGINS, SCREEN, Quantitative Trait, Heritable, Sex Factors, Genetic linkage, medicine, Humans, Bipolar disorder, 030304 developmental biology, Genetic association study, Aged, Genetic Variation, medicine.disease, Genetic Loci, Autism, genetics [Gene Frequency], Developmental Psychopathology, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract: Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.
Published: 2021
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18. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Author: Giuseppe Matullo, John R. B. Perry, Meena Kumari, Gemma C Sharp, Tomáš Paus, E. Giralt-Steinhauer, Marta E. Alarcón-Riquelme, Koen F. Dekkers, F. Gagnon, Simonetta Guarrera, Cilla Söderhäll, Rosie M. Walker, Therese Tillin, M. Smarts, Juan E. Castillo-Fernandez, John M. Starr, Jean Shin, Dan Mason, T Esko, Christopher Shaw, Hannah R Elliott, Manon Bernard, David L. Corcoran, Yvonne Awaloff, Ahmad Al Khleifat, Bert Brunekreef, Clara Viberti, John Wright, Gibran Hemani, Kathryn L. Evans, Camilla Schmidt Morgen, Jouke J. Hottenga, Susan M. Ring, Terrie E. Moffitt, Silva Kasela, C. Hale, Idil Yet, Katri Räikkönen, René Luijk, Vanessa Schmoll, Kimberley Burrows, Annelot M. Dekker, D. VanHeemst, Jordana T. Bell, Jordi Jimenez-Conde, Carlotta Sacerdote, Salvatore Panico, Lili Milani, Nabila Kazmi, Torben Hansen, Aleksey Shatunov, J L Min, Richa Gupta, Henning Tiemeier, Grant W. Montgomery, Vincent W. V. Jaddoe, E.J.C. de Geus, Fernando Rivadeneira, Debbie A Lawlor, Carol A. Wang, Toni-Kim Clarke, Susanne Lucae, Nicholas J. Wareham, Jordi Sunyer, Felix R. Day, C. Soriano-Tarraga, Christoph Bock, Juan R. González, D. Aissi, J.B. van Meurs, Ian J. Deary, Ken K. Ong, Louise Arseneault, Eilis Hannon, Bastiaan T. Heijmans, Philip E. Melton, Ashok Kumar, Pierre-Emmanuel Morange, Zdenka Pausova, T.D. Spector, Nicholas G. Martin, J. Mill, Francesc Català-Moll, Alun D. Hughes, Leonard C. Schalkwyk, Giovanni Cugliari, Carlos Ruiz-Arenas, Elena Carnero-Montoro, Marine Germain, Yanni Zeng, Andrew M. McIntosh, Riccardo E. Marioni, Wilfried Karmaus, Ikram, Gonneke Willemsen, Miina Ollikainen, Karen M Ho, Craig E. Pennell, F.I. Rezwan, Darina Czamara, Ramona A. J. Zwamborn, Dorret I. Boomsma, Wendy L. McArdle, J. M. van Dongen, Guillermo Barturen, Matthew Suderman, Richie Poulton, Daniel Lawson, A. Metspalu, David-Alexandre Trégouët, Marian Beekman, Andrew D. Bretherick, Johanna Klughammer, Hongmei Zhang, M.H. van IJzendoorn, Nish Chaturvedi, Jari Lahti, Karen Sugden, Jan H. Veldink, Mariona Bustamante, Avshalom Caspi, Pooja R. Mandaviya, Judith M. Vonk, Tom R. Gaunt, Cheng-Jian Xu, John W. Holloway, Tian Lin, Tom G. Richardson, Caroline L Relton, Naomi R. Wray, Allan F. McRae, George Davey Smith, Erik Melén, Valentina Iotchkova, Ellen A. Nohr, Jaakko Kaprio, Göran Pershagen, Elisabeth B. Binder, A. al Chalabi, T.J. Gorrie-Stone, K. van Eijk, Gerard H. Koppelman, M. Lerro, Alexia Cardona, Sailalitha Bollepalli, P.E. Slagboom, Thorkild I. A. Sørensen, André G. Uitterlinden, Jaume Roquer, Peter M. Visscher, Janine F. Felix, Martin Kerick, Gail Davies, Rae-Chi Huang, Alfredo Iacoangeli, Alison D. Murray, Helsinki Institute of Life Science HiLIFE, Institute for Molecular Medicine Finland, Epigenetics of Complex Diseases and Traits, Department of Public Health, Department of Psychology and Logopedics, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Groningen Research Institute for Asthma and COPD (GRIAC), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Epidemiology, Internal Medicine, Pediatrics, Child and Adolescent Psychiatry / Psychology, and Clinical Child and Family Studies
Subjects: Multifactorial Inheritance, ADN, Quantitative Trait Loci, Genome-wide association study, VARIANTS, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, LINKS, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, Genetic variation, Genetics, WIDE ASSOCIATION, GWAS, Humans, Genetic Predisposition to Disease, Genotip, METAANALYSIS, EQTL, 030304 developmental biology, Epigenesis, SNP ANALYSIS, 0303 health sciences, COMPLEX, dNaM, Chromosome Mapping, DNA, DNA Methylation, Phenotype, Genetic architecture, MODEL, Fenotip, Gene Expression Regulation, DNA methylation, MENDELIAN RANDOMIZATION, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Metilació, Transcriptome, Genètica, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
Published: 2020
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19. Genomic and phenomic insights from an atlas of genetic effects on DNA methylation

Author: Carol A. Wang, Simonetta Guarrera, Avshalom Caspi, Eilis Hannon, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Pooja R. Mandaviya, Koen F. Dekkers, Cheng-Jian Xu, Jari Lahti, Juan E. Castillo-Fernandez, Dan Mason, Dylan Aïssi, Jan H. Veldink, Mariona Bustamante, Melissa C. Smart, Guillermo Barturen, Zdenka Pausova, Jenny van Dongen, Jordi Jimenez-Conde, Craig E. Pennell, Gibran Hemani, Tom R. Gaunt, Camilla Schmidt Morgen, Ken K. Ong, Toni-Kim Clarke, Alexia Cardona, Susanne Lucae, René Luijk, T.J. Gorrie-Stone, Phillip E. Melton, Thorkild I. A. Sørensen, André G. Uitterlinden, Jordana T. Bell, Jouke-Jan Hottenga, Meena Kumari, Francesc Català-Moll, Jonathan Mill, Tõnu Esko, Sailalitha Bollepalli, Dorret I. Boomsma, Torben Hansen, Hongmei Zhang, Yanni Zeng, John Wright, Wilfried Karmaus, Martin Kerick, Carolina Soriano-Tárraga, Jaakko Kaprio, Miina Ollikainen, Eco J. C. de Geus, Jordi Sunyer, Therese Tillin, Juan R. González, Yvonne Awaloff, Faisal I. Rezwan, Karen Sugden, Nicholas G. Martin, Karen M Ho, Andres Metspalu, Marine Germain, Kristel R. van Eijk, Ramona A. J. Zwamborn, George Davey Smith, Judith M. Vonk, Tian Lin, Henning Tiemeier, Grant W. Montgomery, Naomi R. Wray, Rae-Chi Huang, Alfredo Iacoangeli, Wendy L. McArdle, Jean Shin, Michael Lerro, Darina Czamara, Valentina Iotchkova, David-Alexandre Trégouët, Johanna Klughammer, Elena Carnero-Montoro, Pierre-Emmanuel Morange, Andrew M. McIntosh, Gemma C Sharp, Alun D. Hughes, Carlos Ruiz-Arenas, John M. Starr, Riccardo E. Marioni, Peter M. Visscher, Nabila Kazmi, Ian J. Deary, Kathryn L. Evans, Terrie E. Moffitt, Janine F. Felix, Tomáš Paus, Ashok Kumar, Jaume Roquer, Christopher Shaw, Hannah R Elliott, Susan M. Ring, Nish Chaturvedi, Giovanni Cugliari, Ahmad Al Khleifat, Joyce B. J. van Meurs, Kimberley Burrows, Bert Brunekreef, Debbie A Lawlor, Clara Viberti, Louise Arseneault, Silva Kasela, Cilla Söderhäll, Idil Yet, Manon Bernard, Christoph Bock, Vincent W. V. Jaddoe, Felix R. Day, Diana van Heemst, Alison D. Murray, Nicholas J. Wareham, Giuseppe Matullo, John R. B. Perry, Gerard H. Koppelman, M. Arfan Ikram, Ammar Al Chalabi, Gonneke Willemsen, Richie Poulton, Daniel Lawson, Andrew D. Bretherick, Vanessa Schmoll, Carlotta Sacerdote, Annelot M. Dekker, Lili Milani, Fernando Rivadeneira, Erik Melén, John W. Holloway, Gareth E. Davies, Tom G. Richardson, Caroline L Relton, Josine L. Min, Göran Pershagen, Elisabeth B. Binder, Marian Beekman, Chris Haley, Richa Gupta, Bastiaan T. Heijmans, Ellen A. Nohr, Allan F. McRae, Matthew Suderman, Rosie M. Walker, David L. Corcoran, Katri Räikkönen, Marinus H. van IJzendoorn, Eva Giralt-Steinhauer, Leonard C. Schalkwyk, Aleksey Shatunov, and Tim D. Spector
Subjects: Genetics, Regulation of gene expression, 0303 health sciences, Natural selection, dNaM, Biology, Genetic architecture, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Genetic variation, DNA methylation, Trait, 030217 neurology & neurosurgery, DNA, 030304 developmental biology
Abstract: Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.
Published: 2020
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20. Large-scale association analyses identify host factors influencing human gut microbiome composition

Author: Vincent W. V. Jaddoe, Myriam Fornage, Lenore J. Launer, Nicholas J. Timpson, Gwen Falony, Xingrong Liu, Mauro D'Amato, Robert C. Kaplan, Daphna Rothschild, Qi Qibin, Jordana T. Bell, Sara Vieira-Silva, Anna Andreasson, Dmitrii Borisevich, Caroline I. Le Roy, Torben Hansen, Eran Segal, Stefan Weiss, Hocheol Shin, Markus M. Lerch, Larbi Bedrani, André G. Uitterlinden, Serena Sanna, Uwe Völker, Urmo Võsa, Jonathan Thorsen, Matthias Laudes, Henry Völzke, Liesbeth Duijts, Kenneth Croitoru, Adriaan van der Graaf, Juan Antonio Raygoza Garay, Jeroen Raes, Dorret I. Boomsma, Daisy Jonkers, Jee-Young Moon, Søren J. Sørensen, Harm-Jan Westra, David A. Hughes, Tue H. Hansen, Andrew D. Paterson, Aldons J. Lusis, Daniel Keszthelyi, Gareth E. Davies, Wolfgang Lieb, Omer Weissbrod, Georg Homuth, Alexandra Zhernakova, Matthew A. Jackson, Robert D. Burk, Elin Org, Katie A. Meyer, Lars Agréus, Susanna Walter, Malte C. Rühlemann, Ad A.M. Masclee, Torben Jørgensen, Zachary D. Wallen, Kaitlin H Wade, Casey T. Finnicum, Andre Franke, Han-Na Kim, Alexander Kurilshikov, Rob Knight, Elad Barkan, Cornelia M. van Duijn, Hyung Lae Kim, Kyoko Watanabe, Annique Claringbould, Alejandro Arias Vasquez, Joanna Szopinska-Tokov, Richard G. IJzerman, Michael Boehnke, Lude Franke, Zlatan Mujagic, Marie Joossens, Marc Jan Bonder, Tim D. Spector, Frank Ulrich Weiss, Raul Y. Tito, Fernando Rivadeneira, Robert Kraaij, Williams Turpin, Eco J. C. de Geus, Henriette A. Moll, Jun Wang, Jingyuan Fu, Oluf Pedersen, Ayse Demirkan, Fabian Frost, Claire J. Steves, Gonneke Willemsen, Shiraz A. Shah, Markku Laakso, Haydeh Payami, Djawad Radjabzadeh, Daria V. Zhernakova, Hans Bisgaard, Cisca Wijmenga, Corinna Bang, Rodrigo Bacigalupe, Carolina Medina-Gomez, Kreete Lüll, and Jakob Stokholm
Subjects: Genetics, Human gut, Host (biology), Genotype, Genetic variation, Host factors, Genome-wide association study, Microbiome, Biology, Feces
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95×10−10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.
Published: 2020
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21. Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education

Author: Satoko Matsumoto, Catherine Tuvblad, Duarte L. Freitas, Aline Jelenkovic, Ruth J. F. Loos, Amie E. Hwang, Jaakko Kaprio, Fuling Ji, Patrik K. E. Magnusson, Reijo Sund, Sooji Lee, Masumi Sugawara, Dorret I. Boomsma, Judy L. Silberg, Jina Kim, Gonneke Willemsen, Robert Vlietinck, Jennifer R. Harris, Paul Lichtenstein, Hermine H. Maes, Wendy Cozen, José Maia, Clare H. Llewellyn, Lior Abramson, Emanuela Medda, Eric Turkheimer, Tessa L. Cutler, Robert F. Krueger, Catherine Derom, Fazil Aliev, Antti Latvala, Hoe Uk Jeong, Ingunn Brandt, Ariel Knafo-Noam, David A. Butler, Zengchang Pang, John L. Hopper, Thomas M. Mack, Sevgi Y. Öncel, David Mankuta, Karri Silventoinen, Robin P. Corley, Vilhelmina Ullemar, K. Paige Harden, Kimberly J. Saudino, Kelly L. Klump, Feng Ning, William S. Kremen, Tracy L. Nelson, Virgilia Toccaceli, Shandell Pahlen, Joohon Sung, Carol E. Franz, Thorkild I. A. Sørensen, Yoshie Yokoyama, Thomas Sevenius Nilsen, Yoon-Mi Hur, Lorenza Nisticò, Catarina Almqvist, Meike Bartels, Matt McGue, Catharina E. M. van Beijsterveldt, Mami Tanaka, Laura A. Baker, Brooke M. Huibregtse, S. Alexandra Burt, Jooyeon Lee, Elliot M. Tucker-Drob, Michael J. Lyons, Margaret Gatz, Esther Rebato, Abigail Fisher, Keith E. Whitfield, Kırıkkale Üniversitesi, KKÜ, Clinicum, Department of Public Health, University of Helsinki, Department of Social Research (2010-2017), Institute of Criminology and Legal Policy, Institute for Molecular Medicine Finland, Helsinki Inequality Initiative (INEQ), Population Research Unit (PRU), Center for Population, Health and Society, Sociology, HUS Helsinki and Uusimaa Hospital District, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, and APH - Methodology
Subjects: Male, Parents, Netherlands Twin Register (NTR), 0301 basic medicine, LOCI, lcsh:Medicine, Genome-wide association study, CHILDREN, heritability, Quantitative trait, project, 0302 clinical medicine, Medicine and Health Sciences, 2.1 Biological and endogenous factors, 030212 general & internal medicine, Aetiology, Gene–environment interaction, Young adult, Child, lcsh:Science, Pediatric, Multidisciplinary, Parenting, HERITABILITY, twins, 3142 Public health care science, environmental and occupational health, maternal education, TWINS, Child, Preschool, loci, MATERNAL EDUCATION, GROWTH, Female, Genetic Background, PROJECT, Adult, Adolescent, Offspring, growth, Quantitative Trait Loci, Environment, Biology, Quantitative trait locus, Article, Quantitative Trait, Young Adult, 03 medical and health sciences, Quantitative Trait, Heritable, children, Genetics, Humans, Human height, GENOME-WIDE ASSOCIATION, Preschool, Heritable, Nutrition, Prevention, lcsh:R, Infant, Newborn, Infant, Heritability, Newborn, Body Height, Quality Education, 030104 developmental biology, genome-wide association, Variance decomposition of forecast errors, Heritable quantitative trait, Gene-Environment Interaction, lcsh:Q, Demography
Abstract: Kaprio, Jaakko/0000-0002-3716-2455; Huibregtse, Brooke M./0000-0003-0977-7249; Magnusson, Patrik KE/0000-0002-7315-7899; ONCEL, Sevgi YURT/0000-0002-0990-292X; Aliev, Fazil/0000-0001-8357-4699; Silventoinen, Karri/0000-0003-1759-3079; van Beijsterveldt, Toos/0000-0002-6617-4201; Knafo-Noam, Ariel/0000-0003-0613-1960; Latvala, Antti/0000-0001-5695-117X; Loos, Ruth/0000-0002-8532-5087; Bartels, Meike/0000-0002-9667-7555; Sund, Reijo/0000-0002-6268-8117; Willemsen, Gonneke/0000-0003-3755-0236 WOS:000560040700031 PubMed: 32409744 Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis. Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Stockholm County Council (ALF-projects)Stockholm County Council; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation; Swedish Asthma and Allergy Association's Research Foundation; Swedish Research CouncilSwedish Research Council [2017-00641]; Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO) [904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008]; European Research CouncilEuropean Research Council (ERC); Avera Institute, Sioux Falls, South Dakota (USA); KNAW Academy Professor Award [PAH/6635]; ENGAGE - European Network for Genetic and Genomic Epidemiology [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Academy of FinlandAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 308248, 312073, 264146]; Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium); Cancer Research UKCancer Research UK [C1418/A7974]; European UnionEuropean Union (EU) [HEALTH-F4-2007-201413]; BioSHaRE EU [HEALTH-F4-2010-261433, POCI/DES/56834/2004]; Portuguese agency for research (The Foundation for Science and Technology [FCT]); Krkkale University Research Grant: KKU [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; Osaka University's International Joint Research Promotion Program [R01 HD068435, R01 MH062375]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; California Twin Program; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; Carolina African American Twin Study of Aging - National Institute on Aging [1RO1-AG13662-01A2, DA011015, 5T32DA017637, 5T32AG052371]; Michigan State University [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-HD066040]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [11-SPG-2518]; MSU Foundation - National Institute of Mental Health [R01 MH58354, AA023322, HD081437]; Vietnam Era Twin Study of Aging; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; VA San Diego Center of Excellence for Stress and Mental Health; Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs; Global Research Network Program of the National Research Foundation [NRF 2011-220-E00006]; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; West Japan Twins and Higher Order Multiple Births Registry [15H05105]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science; Centre of Research Excellence Grant [1079102]; National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [240994]; [266592] This study was conducted within the CODATwins project (Academy of Finland #266592). The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; Amsterdam Public Health (APH); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA) and the KNAW Academy Professor Award (PAH/6635) to DIB. Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278, 308248, 312073 and 264146 to J Kaprio). Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413, and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology [FCT]). S.Y. oncel and F. Aliev are supported by Krkkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. Colorado Twin Registry is funded byNIDA funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371.; The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). The Texas Twin Project is currently funded by grants AA023322 and HD081437 from the National Institutes of Health. Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1 B00047). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID: 1079102), from the National Health and Medical Research Council. Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo.
Published: 2020
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22. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Joris Deelen, Antonia Trichopoulou, Sara Hägg, Kim Overvad, Elisabete Weiderpass, Iryna O. Fedko, Rudolf Kaaks, Nicola D. Kerrison, Kirsi H. Pietiläinen, Ida Surakka, Veikko Salomaa, Svetlana Stoma, Jaakko Kaprio, Alessandra Allione, Cornelia M. van Duijn, Nicholas G. Martin, Veryan Codd, Olle Melander, Nilesh J. Samani, Josine E. Verhoeven, Anne Tjønneland, Natalia Pervjakova, Domenico Palli, Adam S. Butterworth, Nicholas J. Wareham, María Dolores Chirlaque, P. Eline Slagboom, Massimo Mangino, Pascal P. Arp, Christopher P. Nelson, Brenda W.J.H. Penninx, Jessica L. Buxton, Pietro Ferrari, Tao Jiang, Iiris Hovatta, Taylor K. Loe, N. Charlotte Onland-Moret, Salvatore Panico, Peter Jones, Heiner Boeing, Timothy J. Key, Luca A. Lotta, Miguel Rodríguez-Barranco, Diana van Heemst, Chen Li, Robert A. Scott, Sarah E. Medland, Giuseppe Matullo, Alexessander Couto Alves, Rosario Tumino, Jouke-Jan Hottenga, Ken K. Ong, Vittorio Krogh, Gonneke Willemsen, Andres Metspalu, Eva Albrecht, Elina Sillanpää, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Reedik Mägi, Eros Lazzerini Denchi, Peter M. Nilsson, André G. Uitterlinden, Antonio Agudo, Yuri Milaneschi, Ashley van der Spek, Alessia Russo, Linda Broer, Federico Canzian, Marian Beekman, Grant W. Montgomery, Sophie C Warner, Guy Fagherazzi, Markus Perola, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Robert Karlsson, Tim D. Spector, Paul W. Franks, H. Eka D. Suchiman, Claudia Langenberg, Liher Imaz, Nancy L. Pedersen, Scott D. Gordon, Stephen E. Hamby, J. Ramón Quirós, Yvonne T. van der Schouw, Concha Moreno, Christian Gieger, Pekka Jousilahti, Dorret I. Boomsma, Marc J. Gunter, Benjamin Miraglio, Gianluca Severi, John Danesh, UNIVERSITY OF OULU, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Sociology and Social Gerontology, Li, Chen [0000-0002-6423-6325], Ong, Kenneth [0000-0003-4689-7530], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Abdominal Center, Department of Medicine, Endokrinologian yksikkö, Clinicum, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Department of Psychology and Logopedics, Genetics, SLEEPWELL Research Program, Department of Public Health, Mind and Matter, Internal Medicine, and Epidemiology
Subjects: Netherlands Twin Register (NTR), Limfomes, LOCI, Genome-wide association study, Disease, VARIANTS, DISEASE, 0302 clinical medicine, Leukocytes, telomere length, GWAS, Genetics(clinical), Càncer, Mendelian randomisation, Thyroid cancer, Genetics (clinical), 11 Medical and Health Sciences, Cancer, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Telòmer, age-related disease, biological aging, Humans, Nucleotides, Genome-Wide Association Study, Telomere, meta-analyysi, genomiikka, Genomics, CANCER, 3. Good health, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Medical genetics, Biomarker (medicine), HEART, Lymphomas, Life Sciences & Biomedicine, Medical Genetics, medicine.medical_specialty, GENES, DATABASE, Age-related Disease, Biological Aging, Mendelian Randomisation, Telomere Length, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Journal Article, 030304 developmental biology, Medicinsk genetik, Science & Technology, 06 Biological Sciences, medicine.disease, Genòmica, ikääntyminen, 1182 Biochemistry, cell and molecular biology, telomeerit, biological
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020
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23. Causes of variation in food preference in the Netherlands

Author: Edith J. M. Feskens, Kirsten J. M. van Hooijdonk, Jacqueline M. Vink, Dorret I. Boomsma, Gonneke Willemsen, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, and APH - Methodology
Subjects: Netherlands Twin Register (NTR), Adult, Male, 0301 basic medicine, liking, Twins, Food consumption, Biology, heritability, Food preference, Structural equation modeling, Food Preferences, 03 medical and health sciences, Vegetables, Humans, Food science, Sugar, Genetics (clinical), twin-family, Netherlands, VLAG, Global Nutrition, Wereldvoeding, 030109 nutrition & dietetics, business.industry, Genetic vulnerability, digestive, oral, and skin physiology, Obstetrics and Gynecology, Feeding Behavior, Heritability, Preference, 030104 developmental biology, Fruit, Pediatrics, Perinatology and Child Health, Food processing, Female, business, Developmental Psychopathology
Abstract: Contains fulltext : 221836.pdf (Publisher’s version ) (Open Access) Our current society is characterized by an increased availability of industrially processed foods with high salt, fat and sugar content. How is it that some people prefer these unhealthy foods while others prefer more healthy foods? It is suggested that both genetic and environmental factors play a role. The aim of this study was to (1) identify food preference clusters in the largest twin-family study into food preference to date and (2) determine the relative contribution of genetic and environmental factors to individual differences in food preference in the Netherlands. Principal component analysis was performed to identify the preference clusters by using data on food liking/disliking from 16,541 adult multiples and their family members. To estimate the heritability of food preference, the data of 7833 twins were used in structural equation models. We identified seven food preference clusters (Meat, Fish, Fruits, Vegetables, Savory snacks, Sweet snacks and Spices) and one cluster with Drinks. Broad-sense heritability (additive [A] + dominant [D] genetic factors) for these clusters varied between .36 and .60. Dominant genetic effects were found for the clusters Fruit, Fish (males only) and Spices. Quantitative sex differences were found for Meat, Fish and Savory snacks and Drinks. To conclude, our study convincingly showed that genetic factors play a significant role in food preference. A next important step is to identify these genes because genetic vulnerability for food preference is expected to be linked to actual food consumption and different diet-related disorders. 9 p.
Published: 2020
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24. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Author: Jens Treutlein, James B. Potash, Cheynna A. Crowley, Paul F. O'Reilly, Francis M. Mondimore, Nicholas G. Martin, Jodie N. Painter, Qingqin S. Li, Tõnu Esko, Michael Conlon O'Donovan, Markus M. Nöthen, Toni-Kim Clarke, Roseann E. Peterson, Shantel Weinsheimer, Naomi R. Wray, Marie Bækvad-Hansen, Pamela F.A. Madden, Johannes H. Smit, Gonneke Willemsen, Thomas Hansen, Andrew C. Heath, Carsten Horn, Udo Dannlowski, Fulai Jin, Robert A. Schoevers, Jian Yang, Nicholas Eriksson, Marianne Giørtz Pedersen, Patrik K. E. Magnusson, Hans J. Grabe, Michael Gill, Lili Milani, Caroline Hayward, Shaun Purcell, Stanley I. Shyn, Penelope A. Lind, Giorgio Pistis, Michel G. Nivard, Thorgeir E. Thorgeirsson, Abdel Abdellaoui, Andres Metspalu, David J. Porteous, Anders D. Børglum, Christine Søholm Hansen, Scott D. Gordon, Nicholas John Craddock, Susanne Lucae, Douglas Blackwood, Jürgen Wellmann, Till M.F. Andlauer, Wesley K. Thompson, Chao Tian, Rudolf Uher, Nese Direk, Yuri Milaneschi, Paola Giusti-Rodríguez, Rick Jansen, Marcus Ising, Yang Wu, Jesper Krogh, Merete Nordentoft, Jouke-Jan Hottenga, Robert Maier, Ming Hu, Kari Stefansson, Glyn Lewis, Peter McGuffin, Wolfgang Maier, Erin C. Dunn, Bradley T. Webb, Gerome Breen, Henning Teismann, Eric Jorgenson, Jorge A. Quiroz, Brenda W.J.H. Penninx, Jonas Bybjerg-Grauholm, Warren W. Kretzschmar, Dean F. MacKinnon, Craig A. Stockmeier, Wouter J. Peyrot, Enrico Domenici, E. C.J. De Geus, Alexander Teumer, Henry Völzke, Yihan Li, Michael John Owen, Manuel Mattheisen, Bernard Ng, Baptiste Couvy-Duchesne, Daniel J. Smith, Jana Strohmaier, Vassily Trubetskoy, Volker Arolt, Douglas F. Levinson, Futao Zhang, Daniel Umbricht, Aartjan F.T. Beekman, David A. Hinds, Bernhard T. Baune, Henning Tiemeier, Hualin S. Xi, Hamdi Mbarek, Steven P. Hamilton, Stefan Kloiber, Fernando S. Goes, Jianxin Shi, Marcella Rietschel, Dale R. Nyholt, Zoltán Kutalik, Niamh Mullins, Grant W. Montgomery, Henriette N. Buttenschøn, Georg Homuth, Katharina Domschke, Alexander Viktorin, Hilary K. Finucane, Ashley R. Winslow, Saira Saeed Mirza, Fabian Streit, Erik Pettersson, Martin Preisig, Danielle Posthuma, Stephan Ripke, Lucía Colodro-Conde, Thalia C. Eley, Pippa A. Thomson, Thomas Werge, Enrique Castelao, Klaus Berger, Yun Li, Stacy Steinberg, Dorret I. Boomsma, Matthias Nauck, Sara Mostafavi, Jacqueline M. Lane, Katherine E. Tansey, Divya Mehta, Gregory E. Crawford, Andreas J. Forstner, Jane H. Christensen, Silviu Alin Bacanu, Julia Kraft, David M. Hougaard, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Sarah E. Medland, Per Qvist, Kenneth S. Kendler, Jordan W. Smoller, J. Raymond DePaulo, Ian J. Deary, Thomas G. Schulze, Julien Bryois, Ian B. Hickie, Helena Gaspar, Jonathan Mill, James A. Knowles, Cathryn M. Lewis, Hassan S. Dashti, Stefan Herms, Margarita Rivera, John P. Rice, Lynsey S. Hall, Eilis Hannon, Nancy L. Pedersen, Eva C. Schulte, Hreinn Stefansson, Maciej Trzaskowski, André G. Uitterlinden, Bertram Müller-Myhsok, Gail Davies, Mark Adams, Jakob Grove, Eske M. Derks, Sven Cichon, Jonathan I.R. Coleman, Sandra Van der Auwera, Myrna M. Weissman, Preben Bo Mortensen, Josef Frank, Enda M. Byrne, Esben Agerbo, Engilbert Sigurdsson, Xiaoxiao Liu, Patrick F. Sullivan, Carsten Bøcker Pedersen, Ole Mors, Catherine Schaefer, Richa Saxena, Albert M. van Hemert, Jonathan Marchini, Hogni Oskarsson, Franziska Degenhardt, Tracy Air, Elisabeth B. Binder, Christel M. Middeldorp, Farnush Hassan Farhadi Kiadeh, Conor V. Dolan, Sara A. Paciga, Per Hoffmann, Leina Lu, Andrew M. McIntosh, Tim B. Bigdeli, Stephanie H. Witt, Matthew Traylor, Grant Sinnamon, Brien P. Riley, Roy H. Perlis, Patrick J. McGrath, Craig L. Hyde, Ling Shen, Na Cai, Yunpeng Wang, Evelin Mihailov, Isaac S. Kohane, APH - Mental Health, Adult Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Integrative Neurophysiology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Reproduction & Development (AR&D), Human genetics, Epidemiology and Data Science, APH - Digital Health, Epidemiology, Child and Adolescent Psychiatry / Psychology, Internal Medicine, eQTLGen, 23andMe, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Schizophrenia/genetics, LD SCORE REGRESSION, LOCI, Genome-wide association study, Bioinformatics, 0302 clinical medicine, Risk Factors, POLYGENIC RISK, Depression (differential diagnoses), 3. Good health, Phenotype, Schizophrenia, Meta-analysis, MENDELIAN RANDOMIZATION, Genome-Wide Association Study/methods, Major depressive disorder, Female, Depressive Disorder, Major/genetics, EUROPE 2010, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, ddc:570, MENTAL-DISORDERS, Mendelian randomization, SYSTEMATIC ANALYSIS, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, METAANALYSIS, EDUCATIONAL-ATTAINMENT, Depressive Disorder, Major, Case-control study, Case-Control Studies, medicine.disease, Genetic architecture, BODY-MASS INDEX, 030104 developmental biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened\ud risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified\ud 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and\ud implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved\ud in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression\ud with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were\ud putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry\ud lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression\ud and imply that a continuous measure of risk underlies the clinical phenotype.
Published: 2018
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25. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author: Seyhan Yazar, M. Arfan Ikram, Gonneke Willemsen, Maria Pina Concas, Manfred Kayser, Tim D. Spector, David M. Evans, Nicholas G. Martin, David L. Duffy, Changqing Zeng, Bochao D. Lin, Daniela Toniolo, Pirro G. Hysi, Gibran Hemani, Jouke-Jan Hottenga, Paolo Gasparini, Gu Zhu, Sarah E. Medland, Cornelia M. van Duijn, Mario Falchi, Marco Brumat, Nicholas A. Furlotte, Alessia Visconti, André G. Uitterlinden, Cinzia Sala, George McMahon, David A. Hinds, Dorret I. Boomsma, Ilaria Gandin, Ana M. Valdes, Dragana Vuckovic, Giorgia Girotto, Veronique Bataille, Massimiliano Cocca, David A. Mackey, Susan M. Ring, Fan Liu, Tamar Nijsten, Scott D. Gordon, Yan Chen, George Davey Smith, Merel A. Hamer, Antonietta Robino, Alex W. Hewitt, Genetic Identification, Erasmus MC other, Epidemiology, Internal Medicine, Dermatology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Hysi, Pirro G., Valdes, A. M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, Mcmahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., Hinds, David A., Kayser, Manfred, and Spector, Timothy D.
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Black hair, Genetic variation, Genotype, Genetics, Eye color, otorhinolaryngologic diseases, Journal Article, Humans, Hair Color, Aged, Chromosomes, Human, X, Autosome, integumentary system, Heritability, Middle Aged, 030104 developmental biology, Phenotype, Evolutionary biology, Genetic Loci, Female, sense organs, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
Published: 2018
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26. Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Author: Jennie Hui, Joana A. Revez, Simon Phipps, Nicholas G. Martin, Philip J. Thompson, Rick Jansen, L. Bain, Brenda W.J.H. Penninx, Peter N. Le Souëf, Alan James, Cristina Teixeira Vicente, Grant W. Montgomery, Svetlana Baltic, David A. Hinds, Melanie C. Matheson, Colin F. Robertson, Manuel A. R. Ferreira, Dorret I. Boomsma, Joyce Y. Tung, John L. Hopper, Gonneke Willemsen, Rhiannon B. Werder, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Digital Health
Subjects: 0301 basic medicine, Genetics, Netherlands Twin Register (NTR), Linkage disequilibrium, Immunology, Genome-wide association study, Single-nucleotide polymorphism, Quantitative trait locus, Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, SDG 3 - Good Health and Well-being, CLK3, Expression quantitative trait loci, Immunology and Allergy, Human medicine, Cell activation, 030217 neurology & neurosurgery, Genetic association
Abstract: Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both . cis- and . trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results: We tested the association between asthma and 17,190 genes that were found to have . cis- and/or . trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, . LIMS1, . TINF2, and . SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: . B4GALT3, . USMG5, . P2RY13, and . P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. Conclusion: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.
Published: 2017
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27. Heritability and GWAS Studies for Monocyte-Lymphocyte Ratio

Author: Bochao D. Lin, Gonneke Willemsen, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Iryna O. Fedko, E.J.C. de Geus, Dorret I. Boomsma, Rick Jansen, C. Kluft, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, and APH - Methodology
Subjects: Adult, Genetic Markers, Male, 0301 basic medicine, Netherlands Twin Register (NTR), Linkage disequilibrium, Quantitative Trait Loci, Population, Single-nucleotide polymorphism, Genome-wide association study, chemical and pharmacologic phenomena, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Monocytes, Body Mass Index, 03 medical and health sciences, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Journal Article, Humans, Inositol 1,4,5-Trisphosphate Receptors, Genetic Predisposition to Disease, Lymphocytes, Receptors, Lysophosphatidic Acid, education, Genetics (clinical), Genetics, education.field_of_study, Smoking, fungi, Obstetrics and Gynecology, hemic and immune systems, Middle Aged, Heritability, Genetic architecture, 030104 developmental biology, Interferon Regulatory Factors, Pediatrics, Perinatology and Child Health, Expression quantitative trait loci, Female, Integrin alpha Chains, Genome-Wide Association Study
Abstract: The monocyte–lymphocyte ratio (MLR) is a useful biomarker for disease development, but little is known about the extent to which genetic and environmental factors influence MLR variation. Here, we study the genetic architecture of MLR and determine the influence of demographic and lifestyle factors on MLR in data from a Dutch non-patient twin-family population. Data were obtained in 9,501 individuals from the Netherlands Twin Register. We used regression analyses to determine the effects of age, sex, smoking, and body mass index (BMI) on MLR and its subcomponents. Data on twins, siblings and parents (N = 7,513) were analyzed by genetic structural equation modeling to establish heritability and genome wide single nucleotide polymorphism (SNP) data from a genotyped subsample (N = 5,892) and used to estimate heritability explained by SNPs. SNP and phenotype data were also analyzed in a genome-wide association study to identify the genes involved in MLR. Linkage disequilibrium (LD) score regression and expression quantitative trait loci (eQTL) analyses were performed to further explore the genetic findings. Results showed that age, sex, and age × sex interaction effects were present for MLR and its subcomponents. Variation in MLR was not related to BMI, but smoking was positively associated with MLR. Heritability was estimated at 40% for MLR, 58% for monocyte, and 58% for lymphocyte count. The Genome-wide association study (GWAS) identified a locus on ITGA4 that was associated with MLR and only marginally significantly associated with monocyte count. For monocyte count, additional genetic variants were identified on ITPR3, LPAP1, and IRF8. For lymphocyte count, GWAS provided no significant findings. Taking all measured SNPs together, their effects accounted for 13% of the heritability of MLR, while all known and identified genetic loci explained 1.3% of variation in MLR. eQTL analyses showed that these genetic variants were unlikely to be eQTLs. In conclusion, variation in MLR level in the general population is heritable and influenced by age, sex, and smoking. We identified gene variants in the ITGA4 gene associated with variation in MLR. The significant SNP-heritability indicates that more genetic variants are likely to be involved.
Published: 2017
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28. Short communication: Genetic association between schizophrenia and cannabis use

Author: Michel G. Nivard, Dorret I. Boomsma, Jacqueline M. Vink, Alberto Sainz Cort, Nathan A. Gillespie, Karin J. H. Verweij, Abdel Abdellaoui, Lannie Ligthart, Gonneke Willemsen, Camelia C. Minică, Jouke-Jan Hottenga, Harmen H.M. Draisma, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Methodology, and Academic Medical Center
Subjects: Netherlands Twin Register (NTR), Adult, Male, Multifactorial Inheritance, medicine.medical_specialty, Adolescent, Marijuana Smoking, Toxicology, Genetic correlation, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Journal Article, Diseases in Twins, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Pharmacology (medical), Registries, Psychiatry, Aged, Netherlands, Genetic association, Aged, 80 and over, Pharmacology, biology, Middle Aged, Cannabis use, medicine.disease, biology.organism_classification, Regression, 030227 psychiatry, Psychiatry and Mental health, Phenotype, Sample size determination, Schizophrenia, Female, Cannabis, Psychology, Developmental Psychopathology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Item does not contain fulltext Background and aim: Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. Methods: Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation. Results: Polygenic risk scores for schizophrenia were significantly (alpha
Published: 2017
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29. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author: Christian Gieger, Teemu Palviainen, Bettina Konte, Peter P. Pramstaller, Aarno Palotie, Elisabeth Widen, Monique M.B. Breteler, Caroline Hayward, Xin Li, Tim D. Spector, Jing Hua Zhao, John M. Starr, David M. Evans, Nicholas G. Martin, Wendy L. McArdle, Nicole Soranzo, Mads Melbye, Peter Kraft, André G. Uitterlinden, Beate St Pourcain, Massimo Mangino, Daniel I. Chasman, Jacques S. Beckmann, Gabriel Cuellar Partida, George Davey Smith, Cecilia M. Lindgren, Johan G. Eriksson, Alan F. Wright, Kauko Heikkilä, Eva Albrecht, Gudmar Thorleifsson, Mari Nelis, Nicholas Eriksson, Dawn M. Waterworth, Leena Peltonen, Frank J. A. van Rooij, Jari Lahti, Maris Teder-Laving, Igor Rudan, Annette M. Hartmann, Guillaume Paré, Ole A. Andreassen, Mohammad Arfan Ikram, Stacy Steinberg, Bjarke Feenstra, Peter Vollenweider, Sarah E. Medland, Brenda W.J.H. Penninx, Mark I. McCarthy, Jordan W. Smoller, Fazil Aliev, Joel N. Hirschhorn, Dan Rujescu, J.M. Vink, Dorret I. Boomsma, Harry Campbell, Pedro Marques-Vidal, David A. Hinds, Tõnu Esko, Ruth J. F. Loos, Zoltán Kutalik, Jouke-Jan Hottenga, Reedik Mägi, Dale R. Nyholt, Kari Stefansson, Kevin S. O’Connell, Hreinn Stefansson, Scott Melville, Andres Metspalu, Inês Barroso, Marco P. Boks, Gail Davies, Lavinia Paternoster, Thomas Hansen, Norman Klopp, H.-Erich Wichmann, David L. Duffy, Lili Milani, Heather A. Boyd, Michelle Luciano, Benjamin M. Neale, Margaret J. Wright, Fernando Rivadeneira, Liang-Dar Hwang, Scott D. Gordon, Jiali Han, Jennifer E. Huffman, Danielle M. Dick, Roel A. Ophoff, Ozren Polasek, Nicholas J. Wareham, Vincent Mooser, Mousheng Xu, Johannes H. Smit, Gonneke Willemsen, Ian J. Deary, Panos Deloukas, John P. Kemp, Cornelia M. van Duijn, Samuli Ripatti, Joyce Y. Tung, Eco J. C. de Geus, Cameron D. Palmer, Ina Giegling, Katri Räikkönen, Thomas Werge, Eero Vuoksimaa, Andrew A. Hicks, Inga Prokopenko, Lynn Cherkas, Sigurdur H. Magnusson, Gérard Waeber, Nicholas J. Timpson, Frank Geller, Carolina Medina-Gomez, Nicole M. Warrington, Kay-Tee Khaw, and Jaakko Kaprio
Subjects: Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetic variants, Biology, Association (psychology), Biobank, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.
Published: 2019
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30. Metabolomics reveals a link between homocysteine and lipid metabolism and leukocyte telomere length: the ENGAGE consortium

Author: Krista Fischer, P. Eline Slagboom, Massimo Mangino, Aaron Isaacs, Christian Gieger, Marian Beekman, Joris Deelen, Diana van Heemst, Sarah E. Medland, Nilesh J. Samani, Nicholas G. Martin, Toomas Haller, Veryan Codd, Cornelia M. van Duijn, René Pool, Najaf Amin, Dale R. Nyholt, Ashley van der Spek, Idil Yet, Rui Wang-Sattler, Dorret I. Boomsma, Harmen Draisma, Ayse Demirkan, Linda Broer, Eva Albrecht, Andres Metspalu, Simon P. Mooijaart, Tim D. Spector, H. Eka D. Suchiman, Anjali K. Henders, John Whitfield, Konstantin Strauch, Anika A. M. Vaarhorst, Mait Raag, Harish Dharuri, Margaret J. Wright, Gonneke Willemsen, Eco J. C. de Geus, Grant W. Montgomery, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, Biochemie, RS: Carim - B01 Blood proteins & engineering, Epidemiology, Internal Medicine, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, Biological Psychology, and APH - Methodology
Subjects: Netherlands Twin Register (NTR), Male, 0301 basic medicine, Homocysteine, Metabolite, lcsh:Medicine, 0601 Biochemistry and Cell Biology, medicine.disease_cause, METHIONINE RESTRICTION, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, PLASMA TOTAL HOMOCYSTEINE, Leukocytes, lcsh:Science, Telomere Shortening, LIFE-SPAN, Multidisciplinary, Middle Aged, Telomere, 3. Good health, Multidisciplinary Sciences, Telomeres, Lysophosphatidylcholine, CARDIOVASCULAR-DISEASE, Low-density lipoprotein, Science & Technology - Other Topics, Female, Adult, medicine.medical_specialty, 0299 Other Physical Sciences, LOW-DENSITY-LIPOPROTEIN, HEART-DISEASE, Biology, FAMILIAL LONGEVITY, Article, WHITE BLOOD-CELLS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, medicine, Metabolomics, Humans, Aged, Science & Technology, Methionine, MORTALITY, lcsh:R, Lipid metabolism, Lipid Metabolism, medicine.disease, ENDOTHELIAL-CELLS, 030104 developmental biology, Endocrinology, chemistry, lcsh:Q, 030217 neurology & neurosurgery, Oxidative stress
Abstract: Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10−6), methionine (p-value = 9.2 × 10−5), tyrosine (p-value = 2.1 × 10−4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10−4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10−4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10−4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.
Published: 2019
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31. The genomic architecture of blood metabolites based on a decade of genome-wide analyses

Author: Aswin Verhoeven, Thomas Hankemeier, P. Eline Slagboom, Jouke-Jan Hottenga, Pieter Jelle Visser, Iryna O. Fedko, Marian Beekman, Anouk den Braber, Fiona A. Hagenbeek, Abdel Abdellaoui, Gonneke Willemsen, Jenny van Dongen, Cornelia M. van Duijn, Ko Willems van Dijk, René Pool, Michel G. Nivard, Dorret I. Boomsma, Amy C. Harms, Eco J. C. de Geus, Meike Bartels, Harmen H.M. Draisma, and H. Eka D. Suchiman
Subjects: Genetics, chemistry.chemical_compound, Metabolomics, chemistry, Metabolite, Genetic variation, Biology, Heritability, Genome, Phenotype, Genetic architecture, Genetic association
Abstract: Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified > 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N= 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences inh2Metabolite-hitsamong different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higherh2Metabolite-hitsestimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.
Published: 2019
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32. An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis

Author: Jennifer A. Smith, Andrea A. Baccarelli, Jordana T. Bell, James B. Meigs, James S. Pankow, Jun Liu, Ayse Demirkan, Marjolein J. Peters, Jerome I. Rotter, Elias Salfati, Bertha Hidalgo, Audrey Y. Chu, André G. Uitterlinden, Luigi Ferrucci, Pooja R. Mandaviya, Nona Sotoodehnia, Eric A. Whitsel, Liesbeth Duijts, Marie-France Hivert, Elena Carnero-Montoro, Eric J.G. Sijbrands, Ann Zenobia Moore, Janine F. Felix, Jenny van Dongen, Najaf Amin, Tim D. Spector, Oscar H. Franco, Harald Grallert, Tiphaine Martin, Ivana Nedeljkovic, Josée Dupuis, Aaron Isaacs, Themistocles L. Assimes, Pei-Chien Tsai, Cornelia M. van Duijn, Lifang Hou, Daniel Levy, Ko Willems van Dijk, Rahul Gondalia, Samantha Lent, Abbas Dehghan, Rozenn N. Lemaitre, Jan Bressler, Christian Herder, Min A. Jhun, Symen Ligthart, Dorret I. Boomsma, Gonneke Willemsen, Toshiko Tanaka, Rick Jansen, Joyce B. J. van Meurs, Shih-Jen Hwang, Vincent W. V. Jaddoe, Donna K. Arnett, Eco J. C. de Geus, Henning Tiemeier, Stefania Bandinelli, Pediatric surgery, Epidemiology and Data Science, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Epidemiology, Internal Medicine, Pediatrics, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, RS: CARIM - R1 - Thrombosis and haemostasis, RS: FHML MaCSBio, Biochemie, and RS: Carim - B01 Blood proteins & engineering
Subjects: 0301 basic medicine, Epigenomics, Male, Netherlands Twin Register (NTR), medicine.medical_treatment, General Physics and Astronomy, 02 engineering and technology, Type 2 diabetes, UP-REGULATION, Epigenesis, Genetic, Glucose homeostasis, Homeostasis, Insulin, lcsh:Science, Genetics, Aged, 80 and over, Multidisciplinary, Middle Aged, 021001 nanoscience & nanotechnology, 3. Good health, Multidisciplinary Sciences, DNA methylation, Science & Technology - Other Topics, Epigenetics, Female, 0210 nano-technology, WAIST CIRCUMFERENCE, Metabolic Networks and Pathways, Adult, EXPRESSION, Science, 610 Medicine & health, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, TYPE-2, SDG 3 - Good Health and Well-being, 360 Social problems & social services, Diabetes mellitus, medicine, GLYCEMIC TRAITS, Humans, Computer Simulation, Obesity, Transcriptomics, Aged, EPIGENOME-WIDE ASSOCIATION, Science & Technology, Gene Expression Profiling, DIABETES-MELLITUS, General Chemistry, DNA Methylation, medicine.disease, GENE, IRS2, BODY-MASS INDEX, 030104 developmental biology, Glucose, Diabetes Mellitus, Type 2, Gene Expression Regulation, lcsh:Q, CpG Islands, Genome-Wide Association Study, FASTING GLUCOSE
Abstract: Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D., Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.
Published: 2019
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33. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author: David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.
Published: 2019
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34. Multivariate genome-wide analyses of the well-being spectrum

Author: Eco J. C. de Geus, Bart M. L. Baselmans, Margot P van de Weijer, Yanchun Bao, Gonneke Willemsen, Meike Bartels, Hill F. Ip, Michel G. Nivard, Jouke-Jan Hottenga, Melissa C. Smart, Dorret I. Boomsma, Jenny van Dongen, Rick Jansen, Abdel Abdellaoui, Meena Kumari, Adult Psychiatry, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Psychiatry, and Epidemiology and Data Science
Subjects: Netherlands Twin Register (NTR), Multifactorial Inheritance, Multivariate statistics, Multivariate analysis, Quantitative Trait Loci, Gene Expression, Computational biology, Biology, Polymorphism, Single Nucleotide, Genome, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Interneurons, Genetics, Humans, Gene, 030304 developmental biology, 0303 health sciences, Genome, Human, Univariate, Brain, Computational Biology, Human genetics, Phenotype, Meta-analysis, Multivariate Analysis, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.
Published: 2019
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35. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility

Author: Bruno Reversade, Patrik K. E. Magnusson, Isleifur Olafsson, Stacy Steinberg, Nicholas G. Martin, Cornelis B. Lambalk, Hreinn Stefánsson, Jouke-Jan Hottenga, Kari Stefansson, Kerrie McAloney, Tim D. Spector, Scott D. Gordon, Ken K. Ong, Hilary C. Martin, Felix R. Day, Brenda W.J.H. Penninx, Gonneke Willemsen, Matt McGue, R. Alan Harris, Ragnar P. Kristjansson, Rick Jansen, Eco J. C. de Geus, Dale R. Nyholt, William G. Iacono, Dorret I. Boomsma, Grant W. Montgomery, John Perry, Michael B. Miller, Olof Sigurdardottir, Kjersti Aagaard, Robert Plomin, Hamdi Mbarek, Jaakko Kaprio, Gudmundur I. Eyjolfsson, Jacqueline M. Vink, Gareth E. Davies, Allan F. McRae, Day, Felix [0000-0003-3789-7651], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Psychiatry, EMGO - Mental health, Obstetrics and gynaecology, ICaR - Ischemia and repair, Biological Psychology, EMGO+ - Quality of Care, and Center for Reproductive Medicine
Subjects: Netherlands Twin Register (NTR), Male, 0301 basic medicine, media_common.quotation_subject, Mothers, Fertility, Genome-wide association study, Single-nucleotide polymorphism, Anxiety, Biology, FSHB, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Pregnancy, Twins, Dizygotic, Genetics, Humans, Genetics(clinical), Family, Longitudinal Studies, Allele, Genetics (clinical), media_common, 030219 obstetrics & reproductive medicine, Depression, Case-control study, Genetic Variation, Twin study, 3. Good health, 030104 developmental biology, Case-Control Studies, Menarche, Female, Follicle Stimulating Hormone, Developmental Psychopathology, Genome-Wide Association Study, Polycystic Ovary Syndrome, Demography
Abstract: Contains fulltext : 157507.pdf (Publisher’s version ) (Closed access) Spontaneous dizygotic (DZ) twinning occurs in 1%–4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10−9, and rs17293443 in SMAD3, p = 1.57 × 10−8) and replicated (p = 3 × 10−3 and p = 1.44 × 10−4, respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health. 11 p.
Published: 2016
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36. Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study

Author: Esther Rebato, Ginette Dionne, Ariel Knafo-Noam, Glen E. Duncan, Jane Wardle, Zengchang Pang, Sevgi Y. Öncel, Thomas M. Mack, K. Paige Harden, Feng Ning, Dedra Buchwald, Grant W. Montgomery, Michel Boivin, Corrado Fagnani, Thalia C. Eley, Finn Rasmussen, Youngsook Chong, Syuichi Ooki, Frank Vitaro, Morten Sodemann, Henning Beck-Nielsen, Robert Plomin, Xiaohu Ding, Andreas Busjahn, Kimberly J. Saudino, Maria A. Stazi, Morten Bjerregaard-Andersen, Massimo Mangino, Per Tynelius, Yoshie Yokoyama, S. Alexandra Burt, Kerry L. Jang, Ruth J. F. Loos, Jeffrey M. Craig, Wenjing Gao, Gary E. Swan, Brooke M. Huibregtse, Claire M. A. Haworth, Lindon J. Eaves, Sören Möller, Fuling Ji, Christian Kandler, Mingguang He, Gonneke Willemsen, Danshiitsoodol Narandalai, Meike Bartels, Toos C. E. M. van Beijsterveldt, Genevieve Lachance, Richard Saffery, Ruth Krasnow, Kaare Christensen, Robert F. Vlietinck, Jack H. Goldberg, Laura A. Baker, Fazil Aliev, Patrik K. E. Magnusson, Axel Skytthe, Dorret I. Boomsma, Adam Domonkos Tarnoki, Kelly L. Klump, Elliot M. Tucker-Drob, Abigail Fisher, Liming Li, Nicholas G. Martin, David Laszlo Tarnoki, Chika Honda, Matt McGue, Nancy L. Pedersen, Catherine Tuvblad, Kirsten Ohm Kyvik, Wendy Cozen, Jaakko Kaprio, Tim D. Spector, Robin P. Corley, Reijo Sund, David Mankuta, Lise Dubois, Alice M. Gregory, Thorkild I. A. Sørensen, Sari Aaltonen, Duarte L. Freitas, Aline Jelenkovic, Amie E. Hwang, Gombojav Bayasgalan, Robert F. Krueger, David A. Butler, Kauko Heikkilä, Mara Brendgen, Paul Lichtenstein, Hermine H. Maes, Sarah E. Medland, Catherine Derom, Canqing Yu, Judy L. Silberg, José Maia, Tom A. McAdams, Cristina D'Ippolito, Lior Abramson, Clare H. Llewellyn, Karri Silventoinen, Yoon-Mi Hur, Shandell Pahlen, Margaret Gatz, Jacob vB Hjelmborg, Kırıkkale Üniversitesi, Biological Psychology, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Male, 0301 basic medicine, Gerontology, близнецы, Netherlands Twin Register (NTR), Medicine (miscellaneous), индекс массы тела, Body Mass Index, Twins, Dizygotic, genetics, Young adult, Gene–environment interaction, Child, факторы окружающей среды, Nutrition and Dietetics, Asia, Eastern, Age Factors, twins, Europe, Child, Preschool, генетические факторы, Female, Adult, близнецовый метод, Adolescent, Environment, Biology, Affect (psychology), Childhood obesity, Young Adult, 03 medical and health sciences, BMI, Sex Factors, children, SDG 3 - Good Health and Well-being, Genetic variation, Journal Article, medicine, Humans, Obesity, Australia, Twin, Genetic Variation, Infant, Twins, Monozygotic, Heritability, medicine.disease, 030104 developmental biology, Faculdade de Ciências Sociais, North America, Gene-Environment Interaction, international comparisons, Body mass index, Demography
Abstract: Kandler, Christian/0000-0002-9175-235X; Bartels, Meike/0000-0002-9667-7555; Medland, Sarah E/0000-0003-1382-380X; Kaprio, Jaakko/0000-0002-3716-2455; Fagnani, Corrado/0000-0001-5771-7772; de Freitas, Duarte Luis/0000-0001-6642-3370; Hjelmborg, Jacob/0000-0001-9630-9149; mangino, massimo/0000-0002-2167-7470; Busjahn, Andreas/0000-0001-9650-6919; Montgomery, Grant W/0000-0002-4140-8139; Moller, Soren/0000-0003-0858-4269; Heikkila, Kauko/0000-0002-9256-8028; Skytthe, Axel E/0000-0002-8629-4913; Christensen, Kaare/0000-0002-5429-5292; Knafo-Noam, Ariel/0000-0003-0613-1960; ONCEL, Sevgi YURT/0000-0002-0990-292X; Sund, Reijo/0000-0002-6268-8117; Aliev, Fazil/0000-0001-8357-4699; Magnusson, Patrik/0000-0002-7315-7899; Huibregtse, Brooke M./0000-0003-0977-7249; Loos, Ruth J F/0000-0002-8532-5087; Boivin, Michel/0000-0001-8621-9844; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Pahlen, Shandell/0000-0003-0753-4155; van Beijsterveldt, Toos/0000-0002-6617-4201; McAdams, Tom/0000-0002-6825-3499; Sodemann, Morten/0000-0001-8992-2500; Pedersen, Nancy/0000-0001-8057-3543; Derom, Catherine/0000-0001-5574-796X; Plomin, Robert/0000-0002-0756-3629; Rebato, Esther/0000-0003-1221-8501; Saffery, Richard/0000-0002-9510-4181; Harden, Kathryn/0000-0002-1557-6737; Willemsen, Gonneke/0000-0003-3755-0236; Aaltonen, Sari/0000-0002-2873-4263; Silventoinen, Karri/0000-0003-1759-3079; Rasmussen, Finn/0000-0001-7915-7809; Haworth, Claire/0000-0002-8608-289X; Llewellyn, Clare/0000-0002-0066-2827 WOS: 000381870200017 PubMed: 27413137 Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity. CODATwins project (Academy of Finland) [266592]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375, 1R01ESO15150-01, HD081437, AA023322, RC2 HL103416]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; Special Fund for Health Scientific Research in the Public Welfare, China [201502006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015, HD10333]; National Program for Research Infrastructure from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease; Velux Foundation; US NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium); ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4 [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease Genetics grantAcademy of Finland [213506, 129680]; Academy of Finland grantAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Cancer Research UKCancer Research UK [C1418/A7974]; W T Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research Fellowship grant [RF/2/RFG/2008/0145]; Goldsmiths, University of London, United Kingdom; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Medexpert Ltd., Budapest, Hungary; European Research CouncilEuropean Research Council (ERC) [240994, 230374]; Michigan State University; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; MagW/ZonMW grant [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464- 14192]; VU University's Institute for Health and Care Research; Avera Institute, Sioux Falls, SD; Australian National Health and Medical Research Council grantNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children grant [032-2007]; Victorian Government's Operational Infrastructure Support Program; Portuguese agency for research (The Foundation for Science and Technology) [POCI/DES/56834/2004]; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research Council grant [31/D19086]; Kirikkale University Research grantKirikkale University [KKU 2009/43]; TUBITAK grantTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; European CommunityEuropean Community (EC); National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, United Kingdom; National Institute of Mental Health grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; [5T32DA017637-11]; Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: The Boston University Twin Project is funded by grants R01 HD068435 and R01 MH062375 from the NIH to KS. California Twin Program was supported by The California Tobacco-Related Disease Research Program grants 7RT-0134H, 8RT-0107H, and 6RT-0354H and by NIH grant 1R01ESO15150-01. Chinese National Twin Registry is funded by Special Fund for Health Scientific Research in the Public Welfare (Project No: 201502006), China. Colorado Twin Registry is funded by NIDA funded center grant DA011015, and Longitudinal Twin Study HD10333; BMH is supported by to 5T32DA017637-11. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US NIH grant P01 AG08761. Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement 201413; National Institute of Alcohol Abuse and Alcoholism grants AA-12502, AA-00145, and AA-09203 to RJR; the Academy of Finland Center of Excellence in Complex Disease Genetics grants 213506 and 129680; and the Academy of Finland grants 100499, 205585, 118555, 141054, 265240, 263278, and 264146 to JK. KS is supported by Osaka University's International Joint Research Promotion Program. Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Waves 1-3 of Genesis 12-19 were funded by the W T Grant Foundation, the University of London Central Research fund and Medical Research Council Training Fellowship grant G81/343 and Career Development Award G120/635 to TCE. Wave 4 was supported by the Economic and Social Research Council grant RES-000-22-2206 and the Institute of Social Psychiatry (06/07-11) to AMG, who was also supported at that time by a Leverhulme Research Fellowship grant RF/2/RFG/2008/0145. Wave 5 was supported by funding to AMG from Goldsmiths, University of London, United Kingdom. Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China grant 81125007. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Longitudinal Israeli Study of Twins was funded by the Starting Grant 240994 from the European Research Council to AK. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, and R03-MH63851-01 from the National Institute of Mental Health, R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, and 11-SPG-2518 from the MSU Foundation. The NAS-NRC Twin Registry acknowledges financial support from NIH grant R21 AG039572. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, and 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464- 14192; VU University's Institute for Health and Care Research; the European Research Council grant 230374; and the Avera Institute, Sioux Falls, SD.; PETS was supported by the Australian National Health and Medical Research Council grant 437015 and 607358 to JC and RS, the Bonnie Babes Foundation grant BBF20704 to JMC, the Financial Markets Foundation for Children grant 032-2007 to JMC, and by the Victorian Government's Operational Infrastructure Support Program. Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology). The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (MB). South Korea Twin Registry is supported by National Research Foundation of Korea grant NRF-371-2011-1 B00047. The Texas Twin Project is currently funded by grants AA023322 and HD081437 from the NIH. The Twins Early Development Study is supported by program grant G0901245 from the UK Medical Research Council and the work on obesity in the Twins Early Development Study is supported in part by the UK Biotechnology and Biological Sciences Research Council grant 31/D19086. SYO and FA are supported by Kirikkale University Research grant KKU 2009/43 and TUBITAK grant 114C117. TwinsUK was funded by European Community's Seventh Framework Programme grant FP7/2007-2013. The study also receives support from the National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, United Kingdom. The University of Southern California Twin Study is funded by the National Institute of Mental Health grant R01 MH58354. University of Washington Twin Registry was supported in part by grant NIH RC2 HL103416 (D and PI). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) grant 15H05105 from the Japan Society for the Promotion of Science.
Published: 2016
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37. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author: Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Macé, Carlo Sidore, Stella Trompet, Massimo Mangino, Maria Sabater-Lleal, John P. Kemp, Ali Abbasi, Tim Kacprowski, Niek Verweij, Albert V. Smith, Tao Huang, Carola Marzi, Mary F. Feitosa, Kurt K. Lohman, Marcus E. Kleber, Yuri Milaneschi, Christian Mueller, Mahmudul Huq, Efthymia Vlachopoulou, Leo-Pekka Lyytikäinen, Christopher Oldmeadow, Joris Deelen, Markus Perola, Jing Hua Zhao, Bjarke Feenstra, Marzyeh Amini, Jari Lahti, Katharina E. Schraut, Myriam Fornage, Bhoom Suktitipat, Wei-Min Chen, Xiaohui Li, Teresa Nutile, Giovanni Malerba, Jian’an Luan, Tom Bak, Nicholas Schork, Fabiola Del Greco M., Elisabeth Thiering, Anubha Mahajan, Riccardo E. Marioni, Evelin Mihailov, Joel Eriksson, Ayse Bilge Ozel, Weihua Zhang, Maria Nethander, Yu-Ching Cheng, Stella Aslibekyan, Wei Ang, Ilaria Gandin, Loïc Yengo, Laura Portas, Charles Kooperberg, Edith Hofer, Kumar B. Rajan, Claudia Schurmann, Wouter den Hollander, Tarunveer S. Ahluwalia, Jing Zhao, Harmen H.M. Draisma, Ian Ford, Nicholas Timpson, Alexander Teumer, Hongyan Huang, Simone Wahl, YongMei Liu, Jie Huang, Hae-Won Uh, Frank Geller, Peter K. Joshi, Lisa R. Yanek, Elisabetta Trabetti, Benjamin Lehne, Diego Vozzi, Marie Verbanck, Ginevra Biino, Yasaman Saba, Ingrid Meulenbelt, Jeff R. O’Connell, Markku Laakso, Franco Giulianini, Patrik K.E. Magnusson, Christie M. Ballantyne, Jouke Jan Hottenga, Grant W. Montgomery, Fernando Rivadineira, Rico Rueedi, Maristella Steri, Karl-Heinz Herzig, David J. Stott, Cristina Menni, Mattias Frånberg, Beate St. Pourcain, Stephan B. Felix, Tune H. Pers, Stephan J.L. Bakker, Peter Kraft, Annette Peters, Dhananjay Vaidya, Graciela Delgado, Johannes H. Smit, Vera Großmann, Juha Sinisalo, Ilkka Seppälä, Stephen R. Williams, Elizabeth G. Holliday, Matthijs Moed, Claudia Langenberg, Katri Räikkönen, Jingzhong Ding, Harry Campbell, Michele M. Sale, Yii-Der I. Chen, Alan L. James, Daniela Ruggiero, Nicole Soranzo, Catharina A. Hartman, Erin N. Smith, Gerald S. Berenson, Christian Fuchsberger, Dena Hernandez, Carla M.T. Tiesler, Vilmantas Giedraitis, David Liewald, Krista Fischer, Dan Mellström, Anders Larsson, Yunmei Wang, William R. Scott, Matthias Lorentzon, John Beilby, Kathleen A. Ryan, Craig E. Pennell, Dragana Vuckovic, Beverly Balkau, Maria Pina Concas, Reinhold Schmidt, Carlos F. Mendes de Leon, Erwin P. Bottinger, Margreet Kloppenburg, Lavinia Paternoster, Michael Boehnke, A.W. Musk, Gonneke Willemsen, David M. Evans, Pamela A.F. Madden, Mika Kähönen, Zoltán Kutalik, Magdalena Zoledziewska, Ville Karhunen, Stephen B. Kritchevsky, Naveed Sattar, Genevieve Lachance, Robert Clarke, Tamara B. Harris, Olli T. Raitakari, John R. Attia, Diana van Heemst, Eero Kajantie, Rossella Sorice, Giovanni Gambaro, Robert A. Scott, Andrew A. Hicks, Luigi Ferrucci, Marie Standl, Cecilia M. Lindgren, John M. Starr, Magnus Karlsson, Lars Lind, Jun Z. Li, John C. Chambers, Trevor A. Mori, Eco J.C.N. de Geus, Andrew C. Heath, Nicholas G. Martin, Juha Auvinen, Brendan M. Buckley, Anton J.M. de Craen, Melanie Waldenberger, Konstantin Strauch, Thomas Meitinger, Rodney J. Scott, Mark McEvoy, Marian Beekman, Cristina Bombieri, Paul M. Ridker, Karen L. Mohlke, Nancy L. Pedersen, Alanna C. Morrison, Dorret I. Boomsma, John B. Whitfield, David P. Strachan, Albert Hofman, Peter Vollenweider, Francesco Cucca, Marjo-Riitta Jarvelin, J. Wouter Jukema, Tim D. Spector, Anders Hamsten, Tanja Zeller, André G. Uitterlinden, Matthias Nauck, Vilmundur Gudnason, Lu Qi, Harald Grallert, Ingrid B. Borecki, Jerome I. Rotter, Winfried März, Philipp S. Wild, Marja-Liisa Lokki, Michael Boyle, Veikko Salomaa, Mads Melbye, Johan G. Eriksson, James F. Wilson, Brenda W.J.H. Penninx, Diane M. Becker, Bradford B. Worrall, Greg Gibson, Ronald M. Krauss, Marina Ciullo, Gianluigi Zaza, Nicholas J. Wareham, Albertine J. Oldehinkel, Lyle J. Palmer, Sarah S. Murray, Peter P. Pramstaller, Stefania Bandinelli, Joachim Heinrich, Erik Ingelsson, Ian J. Deary, Reedik Mägi, Liesbeth Vandenput, Pim van der Harst, Karl C. Desch, Jaspal S. Kooner, Claes Ohlsson, Caroline Hayward, Terho Lehtimäki, Alan R. Shuldiner, Donna K. Arnett, Lawrence J. Beilin, Antonietta Robino, Philippe Froguel, Mario Pirastu, Tine Jess, Wolfgang Koenig, Ruth J.F. Loos, Denis A. Evans, Helena Schmidt, George Davey Smith, P. Eline Slagboom, Gudny Eiriksdottir, Andrew P. Morris, Bruce M. Psaty, Russell P. Tracy, Ilja M. Nolte, Eric Boerwinkle, Sophie Visvikis-Siest, Alex P. Reiner, Myron Gross, Joshua C. Bis, Lude Franke, Oscar H. Franco, Emelia J. Benjamin, Daniel I. Chasman, Josée Dupuis, Harold Snieder, Abbas Dehghan, Behrooz Z. Alizadeh, H. Marike Boezen, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Emelia Benjamin, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Josh Bis, Nathan Pankratz, Alex Rainer, James G. Wilson, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Terho Lehtimaki, Yalda Jamshidi, Sophie Siest, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey-Smith, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, J. Rotter, Ken Rice, Leslie Lange, Eco de Geus, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, Eline P. Slagboom, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center Groningen [Groningen] (UMCG), University of Isfahan, University of Tartu, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The University of Texas Health Science Center at Houston (UTHealth), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Split, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Process & Energy Laboratory, Delft University of Technology (TU Delft), Grand Lyon : communauté urbaine de Lyon, Interuniversity Cardiology Institute Netherlands, Department of Twin Research and Genetic Epidemiology, King's College London, London, Huazhong University of Science and Technology [Wuhan] (HUST), Division of Statistical Genomics, Washington University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Institut fuer Theoretische Physik (Institut fuer Theoretische Physik), Universität Heidelberg [Heidelberg] = Heidelberg University, Molecular Epidemiology, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Mahidol University [Bangkok], Northwest A and F University, Laboratoire d'Optimisation des Systèmes Industriels (LOSI), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetics and Biophysics, CNR, Naples, Università degli studi di Verona = University of Verona (UNIVR), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], University of Maryland School of Medicine, University of Maryland System, Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Pop. Genetics, CNR, Sassari, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, IT University of Copenhagen (ITU), Robertson Centre for Biostatistics, University of Glasgow, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, King‘s College London, Jinan University [Guangzhou], Institute of Oceanology [China], School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Shardna life science Pula Cagliari, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Medstar Research Institute, Department of Cardiology, Ernst-Moritz-Arndt University, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Department of Epidemiology, Harvard School of Public Health, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Metacohorts Consortium, INEOS Technologies (SWITZERLAND), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, University of Edinburgh, School of Population Health [Crawley, Western Australia], The University of Western Australia (UWA), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), The Scripps Translational Science Institute and Scripps Health, Tulane Center for Cardiovascular Health, Tulane University Health Sciences Center, Centre for Population Health Sciences, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Luleå University of Technology (LUT), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austrian Institute of Technology [Vienna] (AIT), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC), Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC), Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Virginia, Tampere University Hospital, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Department of Pathological Biochemistry, Royal Infirmary, Oxford University, University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Department of neurology, Institute of Metabolic Science, MRC, The Wellcome Trust Centre for Human Genetics [Oxford], Uppsala Universitet [Uppsala], QIMR Berghofer Medical Research Institute, Institute of Genetic Epidemiology [Neuherberg, Germany], Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Schizophrenia Research Institute [Sydney], Department of Genetics, University of North Carolina System (UNC)-University of North Carolina System (UNC), Vrije Universiteit Brussel (VUB), Population Health Sciences and Education, St George's University of London, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Health Sciences and Biocenter Oulu, University of Oulu, Medizinische Klinik und Poliklinik, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institute of Clinical Chemistry and Laboratory Medicine, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Departments of Epidemiology and Nutrition, Institute of Epidemiology [Neuherberg] (EPI), Medical University Graz, Transplantation Laboratory [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], CLinical Psychology, Genetics and Pathology, Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Center For Narcolepsy, Stanford University, Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, University of Maryland School of Medicine [Baltimore, MD, USA], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Stockholm], Stockholm University, University of Bristol [Bristol], Universiteit Leiden, Department of Epidemiology, University of Washington, University of Washington [Seattle], Department of Epidemiology [Rotterdam], University of Groningen [Groningen], Dutch Initiative on Crohn and Colitis (ICC), Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Physiology and Biophysics [Jackson, MS, USA], University of Southern Mississippi (USM), Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Department of Social Medicine, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Mathematical Institute [Oxford] (MI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, LifeLines Cohort Study, CHARGE Inflammation Working Group, Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L. -P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H. R., Wijmenga, C., Amini, M., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y. -H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W. -M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M. F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y. -C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H. -W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K. -H., Stott, D. J., Menni, C., Franberg, M., S, t. Pourcain B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Grossmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. -D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., Mcevoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M. -R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M. -L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Loos, R. J. F., Evans, D. A., Schmidt, H., Slagboom, P. E., Tracy, R. P., Visvikis-Siest, S., Reiner, A. P., Bis, J. C., Franco, O. H., Benjamin, E. J., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Epidemiology, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), VU University medical center, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Digital Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Universität Heidelberg [Heidelberg], University of Verona (UNIVR), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), IT University of Copenhagen, Technical University of Denmark [Lyngby] (DTU), Consiglio Nazionale delle Ricerche (CNR), University of Virginia [Charlottesville], Université de Lausanne (UNIL), University of Oxford [Oxford], University of Newcastle [Australia] (UoN), Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Helmholtz-Zentrum München (HZM), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Universitätsmedizin der Johannes-Gutenberg Universität Mainz, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Cardiff University-Medical Research Council, University of California-University of California, and DE CARVALHO, Philippe
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Bipolar Disorder, LD SCORE REGRESSION, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, inflammatory disorder, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, ta318, International HapMap Project, Child, Genetics (clinical), 2. Zero hunger, Genetics, Genetics & Heredity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biology, system biology, DEPICT, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, C-reactive protein, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, Adolescent, Adult, Aged, Biomarkers, C-Reactive Protein, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Metabolic Networks and Pathways, Schizophrenia, Young Adult, 3. Good health, [SDV] Life Sciences [q-bio], Medical genetics, Biomarker (medicine), Life Sciences & Biomedicine, Human, medicine.medical_specialty, CHARGE Inflammation Working Group, Biology, IMMUNITY, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, CORONARY-HEART-DISEASE, Mendelian Randomization Analysi, 1000 Genomes Project, METAANALYSIS, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, ta1184, Metabolic Networks and Pathway, Biomarker, INSTRUMENTS, 06 Biological Sciences, 030104 developmental biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, LifeLines Cohort Study
Abstract: International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.
Published: 2018
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38. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Author: Karl Everett, Oscar H. Franco, James S. Pankow, Sharon L.R. Kardia, Andrew D. Johnson, Erin B. Ware, Xiuqing Guo, John M. Starr, Eric Boerwinkle, Christopher J. O'Donnell, Cavin K. Ward-Caviness, Ian J. Deary, Marine Germain, Wolfgang Koenig, Christian Gieger, Paul S. de Vries, Anders Franco-Cereceda, Barbara McKnight, Petra Wolf, Nicholas L. Smith, Jennifer E. Huffman, Per Eriksson, Weihong Tang, Kerri L. Wiggins, Min A. Jhun, Abbas Dehghan, Holger Prokisch, Gonneke Willemsen, Jenny van Dongen, Dorret I. Boomsma, Jennifer A. Smith, Wei Zhao, Joyce B. J. van Meurs, Alanna C. Morrison, Annette Peters, Daniel Levy, Melanie Waldenberger, Nona Sotoodenia, Nicholas S. Roetker, Philip S. Wells, Bruce M. Psaty, Pierre-Emmanuel Morange, Hanna M. Björck, André G. Uitterlinden, David-Alexandre Trégouët, Eco J. C. de Geus, Mohsen Ghanbari, Chunyu Liu, Jennifer A. Brody, Lannie Ligthart, Lei Du, W. David Hill, Vinh Truong, Epidemiology, Internal Medicine, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), University of Toronto, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), VU University medical center, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), medicine.medical_specialty, Aging, [SDV]Life Sciences [q-bio], Immunology, 030204 cardiovascular system & hematology, Biology, Fibrinogen, Biochemistry, Hemostatics, Thrombosis and Hemostasis, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Epigenetics, Gene, ComputingMilieux_MISCELLANEOUS, Hemostasis, medicine.diagnostic_test, Age Factors, Cell Biology, Hematology, DNA Methylation, 3. Good health, 030104 developmental biology, Endocrinology, Clotting time, chemistry, Plasminogen activator inhibitor-1, DNA methylation, Erratum, medicine.drug, Partial thromboplastin time
Abstract: Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10−5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
Published: 2018
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39. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author: Peter P. Zandi, Lisa Jones, Aartjan T.F. Beekman, Christine Fraser, Andreas J. Forstner, Nese Direk, Mark Lathrop, Jesper Krogh, Merete Nordentoft, Bradley T. Webb, Yihan Li, Michael Bauer, Qingqin S. Li, Daniel J. Smith, Carsten Horn, Robert C. Thompson, René Breuer, Eli A. Stahl, David A. Collier, Richard Williamson, Boomsma, Dorret, I, Céline S. Reinbold, Laura J. Scott, Manolis Kogevinas, Jacob Lawrence, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Wade H. Berrettini, John B. Vincent, Toni-Kim Clarke, Henry Voelzke, Stacy Steinberg, Hreinn Stefansson, Dean F. MacKinnon, Thorgeir E. Thorgeirsson, Niamh Mullins, Esben Agerbo, Rudolf Uher, Christina M. Hultman, Pamela A. F. Madden, Eva C. Schulte, Matthew Flickinger, Sebastian Zöllner, Kenneth S. Kendler, Urban Ösby, Enrique Castelao, Michael John Owen, Colm O'Dushlaine, Jens Treutlein, Joanna Hauser, Markus M. Noethen, Erin N. Smith, James McKay, Sandra Van der Auwera, Erin C. Dunn, Steven P. Hamilton, Martin Schalling, Helmut Vedder, Katherine Gordon-Smith, Fabio Rivas, Matthias Nauck, James B. Potash, Morten Mattingsdal, Ling Shen, Tim B. Bigdeli, Kimberly Chambert, Volker Arolt, Daniel L. Koller, Annelie Nordin Adolfsson, Na Cai, Nicholas G. Martin, Carlos N. Pato, Georg Homuth, Jonas Bybjerg-Grauholm, Alexander Teumer, Wesley K. Thompson, Hamel Patel, Jian Yang, Margit Burmeister, Frank Bellivier, Jodie N. Painter, Enda M. Byrne, Margarita Rivera, Nicholas John Craddock, Tatiana Foroud, Shaun Purcell, Paul D. Shilling, David Craig, Vanessa Kiyomi Ota, Michael Boehnke, Devin Absher, Stéphane Jamain, Anne Farmer, Yunpeng Wang, Ole Mors, William A. Scheftner, Jack D. Barchas, Robert Maier, Stanley J. Watson, Allan H. Young, Baptiste Couvy-Duchesne, Jakob Grove, Rick Jansen, John P. Rice, Gerome Breen, Eske M. Derks, Ingrid Melle, Tiffany A. Greenwood, Manuel Mattheisen, Bernard Ng, Edward M. Scolnick, Stefan Kloiber, Lili Milani, Yuri Milaneschi, Fermín Mayoral, Engilbert Sigurdsson, Sarah E. Medland, Wolfgang Maier, Alan F. Schatzberg, Myrna M. Weissman, Jun Li, John R. Kelsoe, Eric Jorgenson, Grant C.B. Sinnamon, Preben Bo Mortensen, Jana Strohmaier, William Byerley, Michel G. Nivard, Richard M. Myers, Evelin Mihailov, Gustavo Turecki, Benjamin S. Pickard, Ian J. Deary, Bernhard T. Baune, Marian L. Hamshere, Stephanie H. Witt, Patrick F. Sullivan, Jennifer L. Moran, Farnush Farhadi Hassan Kiadeh, Cathryn M. Lewis, Srdjan Djurovic, Ian B. Hickie, Hans J. Grabe, Helena Gaspar, Francis J. McMahon, Catherine Schaefer, Guy A. Rouleau, Sandra Meier, Derek W. Morris, Tõnu Esko, Wouter J. Peyrot, Markus Schwarz, Silviu-Alin Bacanu, Adam Wright, Melvin G. McInnis, Elaine K. Green, Douglas M. Ruderfer, Danielle Posthuma, Franziska Degenhardt, Per Qvist, Henriette N. Buttenschøn, Jolanta Lissowska, Stephan Ripke, Nicholas Bass, Giorgio Pistis, Emma M. Quinn, Shantel Weinsheimer, Howard J. Edenberg, Sintia Iole Belangero, Charles Curtis, Ashley R. Winslow, Tracy M. Air, Johannes H. Smit, Isaac S. Kohane, Wei Xu, Pamela B. Mahon, Neonila Szeszenia-Dabrowska, Gonneke Willemsen, Ivan Nikolov, Sven Cichon, Gregory E. Crawford, David M. Hougaard, E.J.C. de Geus, Klaus Berger, Evaristus A. Nwulia, Fernando S. Goes, Pablo Cervantes, Udo Dannlowski, Rolf Adolfsson, Thomas G. Schulze, Bruno Etain, Mark J. Adams, Thomas Hansen, Hugh Gurling, Fan Guo Meng, Judith A. Badner, Julien Bryois, Mateus Jose Abdalla Diniz, Rodrigo A. Bressan, Radhika Kandaswamy, Josef Frank, I. Nicol Ferrier, Bertram Mueller-Myhsok, Manuel A. R. Ferreira, Marion Leboyer, Futao Zhang, Valentina Moskvina, Patrik K. E. Magnusson, Laura M. Huckins, Douglas Blackwood, Michael Gill, Jianxin Shi, Dale R. Nyholt, Nancy L. Pedersen, André G. Uitterlinden, Henning Tiemeier, Vassily Trubetskoy, Scott D. Gordon, Ian Jones, Grant W. Montgomery, Martin Preisig, Cristiana Cruceanu, Sara A. Paciga, Lena Backlund, Abdel Abdellaoui, Andres Metspalu, Gunnar Morken, Marcus Ising, Sascha B. Fischer, Lilijana Oruc, Sian Caesar, Sarah Kittel-Schneider, Thalia C. Eley, Vihra Milanova, Thomas Werge, Andrew Heath, Katherine E. Tansey, Thomas W. Muehleisen, Jane H. Christensen, Chunyu Liu, Mikael Landén, Douglas F. Levinson, Julia Kraft, Juergen Wellmann, Coleman, Jonathan R., I, Peng Zhang, Glyn Lewis, Henning Teismann, Hamdi Mbarek, Carsten Bøcker Pedersen, Szabolcs Szelinger, Alexander Viktorin, Paul Brennan, Brenda W.J.H. Penninx, Maciej Trzaskowski, Yang Wu, Katharina Domschke, John Strauss, Hilary K. Finucane, Detelina Grozeva, Peter Holmans, Saira Saeed Mirza, Ole A. Andreassen, John I. Nurnberger, Lynsey S Hall, Till F. M. Andlauer, Sara Mostafavi, Andreas Reif, Joanna M. Biernacka, Christine Søholm Hansen, Hualin S. Xi, Stephen Newhouse, William E. Bunney, Andrew M. McIntosh, Anna Maaser, Enrico Domenici, Shyn, Stanley, I, Gail Davies, Warren W. Kretzschmar, Simone de Jong, Lucía Colodro-Conde, Pippa A. Thomson, Francis M. Mondimore, Martin Hautzinger, Cinnamon S. Bloss, Fabian Streit, James L. Kennedy, Erik Pettersson, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Johannes Schumacher, Kevin A. McGhee, Divya Mehta, Naomi R. Wray, Robert A. Schoevers, John A. Rice, Jordan W. Smoller, Anders D. Børglum, Susanne Lucae, Jorge A. Quiroz, Daniel Umbricht, Jouke-Jan Hottenga, Kari Stefansson, Marcella Rietschel, Zoltán Kutalik, Sarah E. Bergen, Paul F. O'Reilly, Amanda Dobbyn, Michael Conlon O'Donovan, Falk W. Lohoff, Caroline M. Nievergelt, David J. Porteous, Matthew Traylor, Brien P. Riley, Roy H. Perlis, J. Raymond DePaulo, Martin Alda, James A. Knowles, Cristiano Noto, Keith Matthews, Mark A. Frye, Patrick J. McGrath, Roseann E. Peterson, David St Clair, Roel A. Ophoff, William Coryell, Peter McGuffin, Andiara Calado Saloma Rodrigues, Elliot S. Gershon, Conor V. Dolan, Janice M. Fullerton, Weihua Guan, Niklas Långström, Pamela Sklar, Paul Lichtenstein, Per Hoffmann, Ary Gadelha, Alan W. McLean, Andrew McQuillin, Philip B. Mitchell, Huda Akil, Piotr M. Czerski, Michael Steffens, Hogni Oskarsson, Soumya Raychaudhuri, Marcos L. Santoro, Elisabeth B. Binder, Christel M. Middeldorp, Jose G. Para, Jurgen Del-Favero, Vishwajit L. Nimgaonkar, Peter R. Schofield, Stefan Herms, Marie Bækvad-Hansen, Andrea Pfennig, Albert M. van Hemert, Jutta Kammerer-Ciernioch, Adebayo Anjorin, Sara Paciga, William Lawson, George Kirov, Aiden Corvin, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Jonathan Marchini, Markus Leber, Maria Hipolito, Louise Frisén, Margitta Borrmann-Hassenbach, Amanda Elkin, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Blackwood, DHR, Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, FFH, Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, EJC, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, PAF, Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Børglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G., Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landén, M., Schalling, M., Osby, U., Backlund, L., Frisén, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruč, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Mühleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zöllner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, K., Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., Andreassen, O.A., Mattingsdal, M., Bass, N.J., Gurling, H., McQuillin, A., Breuer, R., Hultman, C., Lichtenstein, P., Huckins, L.M., Leboyer, M., Lathrop, M., Nurnberger, J., Steffens, M., Foroud, T.M., Berrettini, W.H., Craig, D.W., Shi, J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Major Depressive Disorder Bipolar, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Pediatric Surgery, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Internal Medicine
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bipolar Disorder, SAMPLE, Medicine (miscellaneous), Pedigree chart, Disease, 0302 clinical medicine, SCHIZOPHRENIA, 2.1 Biological and endogenous factors, Medicine, Aetiology, ANTICIPATION, lcsh:QH301-705.5, Psychiatry, 0303 health sciences, Depression, ASSOCIATION, Serious Mental Illness, Mental Health, Schizophrenia, Major depressive disorder, General Agricultural and Biological Sciences, Engineering sciences. Technology, medicine.medical_specialty, Context (language use), Article, Psykiatri, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, ddc:570, Behavioral and Social Science, Genetics, PLINK, Genetic Testing, Bipolar disorder, Biology, 030304 developmental biology, business.industry, Prevention, Human Genome, Assortative mating, medicine.disease, Brain Disorders, 030104 developmental biology, Mood, lcsh:Biology (General), Mood disorders, Anticipation (genetics), ONSET, Human medicine, business, 030217 neurology & neurosurgery
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.
Published: 2018
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40. Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs

Author: Meike Bartels, Rick Jansen, Charles E. Breeze, Catharina E.M. van Beijsterveldt, Jouke J. Hottenga, Erik A. Ehli, Bastiaan T. Heijmans, Jenny van Dongen, Noah A. Kallsen, Gonneke Willemsen, Gareth E. Davies, Dorret I. Boomsma, Cornelis Kluft, Shanna A. Peyton, Division 6, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: Netherlands Twin Register (NTR), Male, 0301 basic medicine, lcsh:QH426-470, QTL, Quantitative Trait Loci, Buccal swab, Quantitative trait locus, Biology, Buccal, 03 medical and health sciences, chemistry.chemical_compound, 450 k, 0302 clinical medicine, Illumina, Genetics, Humans, Epigenetics, Child, Children, Molecular Biology, DNA methylation, Mouth Mucosa, Array, Infant, Twin study, Twins, Monozygotic, Methylation, lcsh:Genetics, 030104 developmental biology, Histone, chemistry, Child, Preschool, biology.protein, Female, EPIC, 030217 neurology & neurosurgery, DNA, Genome-Wide Association Study
Abstract: Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1–10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p −16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p −16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.
Published: 2018
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41. Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author: Johannes, Waage, Marie, Standl, John A, Curtin, Leon E, Jessen, Jonathan, Thorsen, Chao, Tian, Nathan, Schoettler, Carlos, Flores, Abdel, Abdellaoui, Tarunveer S, Ahluwalia, Alexessander C, Alves, Andre F S, Amaral, Josep M, Antó, Andreas, Arnold, Amalia, Barreto-Luis, Hansjörg, Baurecht, Catharina E M, van Beijsterveldt, Eugene R, Bleecker, Sílvia, Bonàs-Guarch, Dorret I, Boomsma, Susanne, Brix, Supinda, Bunyavanich, Esteban G, Burchard, Zhanghua, Chen, Ivan, Curjuric, Adnan, Custovic, Herman T, den Dekker, Shyamali C, Dharmage, Julia, Dmitrieva, Liesbeth, Duijts, Markus J, Ege, W James, Gauderman, Michel, Georges, Christian, Gieger, Frank, Gilliland, Raquel, Granell, Hongsheng, Gui, Torben, Hansen, Joachim, Heinrich, John, Henderson, Natalia, Hernandez-Pacheco, Patrick, Holt, Medea, Imboden, Vincent W V, Jaddoe, Marjo-Riitta, Jarvelin, Deborah L, Jarvis, Kamilla K, Jensen, Ingileif, Jónsdóttir, Michael, Kabesch, Jaakko, Kaprio, Ashish, Kumar, Young-Ae, Lee, Albert M, Levin, Xingnan, Li, Fabian, Lorenzo-Diaz, Erik, Melén, Josep M, Mercader, Deborah A, Meyers, Rachel, Myers, Dan L, Nicolae, Ellen A, Nohr, Teemu, Palviainen, Lavinia, Paternoster, Craig E, Pennell, Göran, Pershagen, Maria, Pino-Yanes, Nicole M, Probst-Hensch, Franz, Rüschendorf, Angela, Simpson, Kari, Stefansson, Jordi, Sunyer, Gardar, Sveinbjornsson, Elisabeth, Thiering, Philip J, Thompson, Maties, Torrent, David, Torrents, Joyce Y, Tung, Carol A, Wang, Stephan, Weidinger, Scott, Weiss, Gonneke, Willemsen, L Keoki, Williams, Carole, Ober, David A, Hinds, Manuel A, Ferreira, Hans, Bisgaard, David P, Strachan, and Klaus, Bønnelykke
Subjects: 0301 basic medicine, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, Genome-wide association study, Human leukocyte antigen, Computational biology, Biology, Genetic pathways, Numbering, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030228 respiratory system, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Genetics, ComputingMethodologies_COMPUTERGRAPHICS
Abstract: In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
Published: 2018

42. Genetic and environmental factors affecting birth size variation: A pooled individual-based analysis of secular trends and global geographical differences using 26 twin cohorts

Author: Gombojav Bayasgalan, Corrado Fagnani, Mara Brendgen, Ruth J. F. Loos, Ingunn Brandt, Tessa L. Cutler, Catherine Derom, Henning Beck-Nielsen, Sonia Brescianini, Keith E. Whitfield, Robert Plomin, Lise Dubois, Danshiitsoodol Narandalai, Robert F. Vlietinck, Kirsi H. Pietiläinen, Jennifer R. Harris, Lior Abramson, Yoon-Mi Hur, Claire M. A. Haworth, Jeffrey M. Craig, Thomas Sevenius Nilsen, Robin P. Corley, Per Tynelius, Zengchang Pang, Kimberly J. Saudino, Shandell Pahlen, Richard J. Rose, Esther Rebato, Ariel Knafo-Noam, Aline Jelenkovic, Ginette Dionne, Frank Vitaro, David Mankuta, David Laszlo Tarnoki, Clare H. Llewellyn, Abigail Fisher, Feng Ning, Karri Silventoinen, Gonneke Willemsen, Jaakko Kaprio, Meike Bartels, Reijo Sund, Morten Bjerregaard-Andersen, Maria Antonietta Stazi, Brooke M. Huibregtse, Syuichi Ooki, Richard Saffery, Catherine E M van Beijsterveldt, Fuling Ji, Tracy L. Nelson, Michel Boivin, Yoshie Yokoyama, Dorret I. Boomsma, Adam Domonkos Tarnoki, Matt McGue, Finn Rasmussen, Morten Sodemann, John L. Hopper, Thorkild I. A. Sørensen, Robert F. Krueger, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Population Research Unit (PRU), Academic Disciplines of the Faculty of Social Sciences, Department of Social Research (2010-2017), Research Units of the Faculty of Social Sciences, Doctoral Programme in Population Health, Doctoral Programme in Clinical Research, Clinicum, Research Programs Unit, Diabetes and Obesity Research Program, Kirsi Hannele Pietiläinen / Principal Investigator, Endokrinologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Jaakko Kaprio / Principal Investigator, Department of Public Health, Center for Population, Health and Society, Sociology, HUS Abdominal Center, and Genetic Epidemiology
Subjects: Male, Netherlands Twin Register (NTR), Internationality, Epidemiology, Twins, Birthweight, BLOOD-PRESSURE, 0302 clinical medicine, Twins, Dizygotic, LENGTH, birth length, Birth Weight, genetics, 030212 general & internal medicine, Gene–environment interaction, RISK, OUTCOMES, 030219 obstetrics & reproductive medicine, Geography, General Medicine, Variance (accounting), twins, 3142 Public health care science, environmental and occupational health, Genetic Epidemiology, GROWTH, Female, PRETERM BIRTH, Dizygotic twin, Birth weight, UNITED-STATES, Biology, Environment, pooled studies, 03 medical and health sciences, AGE, Genetic variation, Genetics, Humans, ponderal index, RATES, Birth length, Pooled studies, Twins, Monozygotic, Twin study, Genetic architecture, Body Height, Secular variation, Ponderal index, Gene-Environment Interaction, WEIGHT, Demography
Abstract: Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birth weight, length, and ponderal index (PI) across geographic-cultural regions (Europe, North-America and Australia, and East-Asia) and across birth cohorts and how gestational age modifies these effects.Methods: Data from 26 twin cohorts in 16 countries including 57613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modeling.Results: The variance of birth weight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased the proportions of shared environmental variance and increased the propositions of unique environmental variance. Genetic variance was similar in the geographic-cultural regions, but shared environmental variance was smaller in East-Asia than in Europe and North-America and Australia. The total variance and shared environmental variance of birth length and PI were greater from the birth cohort 1990-1999 onwards compared with the birth cohorts from 1970-1979 to 1980-1989.Conclusion: The contribution of genetic factors to birth size is smaller than that of shared environmental factors, which is partly explained by gestational age. Shared environmental variances of birth length and PI were greater in the latest birth cohorts and differed also across geographic-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time.
Published: 2018
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43. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author: Eugene R. Bleecker, Carlos Flores, Gonneke Willemsen, Kamilla Kjærgaard Jensen, Herman T. den Dekker, Zhanghua Chen, W. James Gauderman, Xingnan Li, Teemu Palviainen, Christian Gieger, Franz Rüschendorf, Dan L. Nicolae, Leon Eyrich Jessen, Hans Bisgaard, Nicole Probst-Hensch, Medea Imboden, Raquel Granell, Ingileif Jonsdottir, Maria Pino-Yanes, Supinda Bunyavanich, Manuel A. R. Ferreira, Michel Georges, Vincent W. V. Jaddoe, Stephan Weidinger, Hongsheng Gui, Esteban G. Burchard, Abdel Abdellaoui, Ivan Curjuric, Johannes Waage, Torben Hansen, Deborah A. Meyers, Rachel A. Myers, Lavinia Paternoster, Ashok Kumar, Ellen A. Nohr, Kari Stefansson, L. Keoki Williams, Andreas Arnold, David P. Strachan, David Torrents, Carol A. Wang, Dorret I. Boomsma, Julia Dmitrieva, Markus J. Ege, Joyce Y. Tung, Jordi Sunyer, Elisabeth Thiering, Nathan Schoettler, Deborah Jarvis, Sílvia Bonàs-Guarch, Joachim Heinrich, Shyamali C. Dharmage, Jaakko Kaprio, Craig E. Pennell, Marie Standl, Philip J. Thompson, Patrick G. Holt, Natalia Hernandez-Pacheco, Angela Simpson, Michael Kabesch, Josep M. Mercader, Marjo-Riitta Järvelin, Andre F.S. Amaral, Tarunveer S. Ahluwalia, Fabián Lorenzo-Díaz, John A. Curtin, Gardar Sveinbjornsson, Susanne Brix, Scott T. Weiss, Chao Tian, Adnan Custovic, David A. Hinds, Amalia Barreto-Luis, John Henderson, Hansjörg Baurecht, Young-Ae Lee, Catharina E. M. van Beijsterveldt, Jonathan Thorsen, Carole Ober, Alexessander Couto Alves, Frank D. Gilliland, Albert M. Levin, Josep M. Antó, Liesbeth Duijts, Erik Melén, Maties Torrent, Klaus Bønnelykke, Göran Pershagen, Epidemiology, Erasmus MC other, Pediatrics, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), HAY-FEVER, Allergy, Genome-wide association study, VARIANTS, Allergic sensitization, 0302 clinical medicine, HLA Antigens, 11 Medical and Health Sciences, Genetics & Heredity, CELL DEVELOPMENT, HERITABILITY, 3. Good health, Phenotype, DISEASES, Hay fever, Life Sciences & Biomedicine, EXPRESSION, Risk, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, DENDRITIC CELLS, 23andMe Research Team, 03 medical and health sciences, Nonallergic rhinitis, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, METAANALYSIS, Science & Technology, RECEPTOR, Genome, Human, AAGC collaborators, Genetic Variation, Allergens, 06 Biological Sciences, medicine.disease, Rhinitis, Allergic, Genetic architecture, 030104 developmental biology, Genetic Loci, Case-Control Studies, Immunology, ASTHMA, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. An Author Correction to this article was published on 16 August 2018. https://www.nature.com/articles/s41588-018-0197-6
Published: 2018
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44. Unraveling the genetic and environmental relationship between well-being and depressive symptoms throughout the lifespan

Author: Bart M. L. Baselmans, Yayouk E. Willems, C. E. M. van Beijsterveldt, Lannie Ligthart, Gonneke Willemsen, Conor V. Dolan, Dorret I. Boomsma, Meike Bartels, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Methodology, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), adulthood, lcsh:RC435-571, Well-being, Biology, heritability, Correlation, Heritability, 03 medical and health sciences, 0302 clinical medicine, depressive symptoms, well-being, lcsh:Psychiatry, Young adult, Depressive symptoms, Original Research, childhood, Psychiatry, Adulthood, Childhood, Adolescence, Psychiatry and Mental health, 030104 developmental biology, Etiology, adolescence, 030217 neurology & neurosurgery, Demography
Abstract: Whether well-being and depressive symptoms can be considered as two sides of the same coin is widely debated. The aim of this study was to gain insight into the etiology of the association between well-being and depressive symptoms across the lifespan. In a large twin-design, including data from 43,427 twins between age 7 and 99, we estimated the association between well-being and depressive symptoms throughout the lifespan and assessed genetic and environmental contributions to the observed overlap. For both well-being (range 31-47%) and depressive symptoms (range 49-61%), genetic factors explained a substantial part of the phenotypic variance across the lifespan. Phenotypic correlations between well-being and depressive symptoms across ages ranged from -0.34 in childhood to -0.49 in adulthood. In children, genetic effects explained 49% of the phenotypic correlation while in adolescents and young adults, genetic effects explained 60-77% of the phenotypic correlations. Moderate to high genetic correlations (ranging from -0.59 to -0.66) were observed in adolescence and adulthood, while in childhood environmental correlations were substantial but genetic correlations small. Our results suggest that in childhood genetic and environmental effects are about equally important in explaining the relationship between well-being and depressive symptoms. From adolescence onwards, the role of genetic effects increases compared to environmental effects. These results provided more insights into the etiological underpinnings of well-being and depressive symptoms, possibly allowing to articulate better strategies for health promotion and resource allocation in the future.
Published: 2018
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45. Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative

Author: Andrew Paterson, Jakob Stokholm, Mauro D'Amato, Eco De Geus, Urmo Võsa, Carolina Medina-Gomez, Malte Rühlemann, Serena Sanna, Jeroen Raes, Jingyuan Fu, Marc Jan Bonder, Claire Steves, Zachary Wallen, Chuan He, Jordana Bell, Frank Ulrich Weiss, Casey Finnicum, Tim Kacprowski, Nicholas Timpson, Joanna Szopinska-Tokov, Williams Turpin, Jonathan Thorsen, Matthew Jackson-Wood, Leon Eyrich Jessen, David Hughes, Elin Org, Hamdi Mbarek, Markus M. Lerch, Gonneke Willemsen, Haydeh Payami, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Internal Medicine, Epidemiology, Erasmus MC other, APH - Methodology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, APH - Health Behaviors & Chronic Diseases, and APH - Personalized Medicine
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Microbiology (medical), GENETICS, 030106 microbiology, Genome-wide association study, Computational biology, Gut flora, Microbiology, lcsh:Microbial ecology, Cohort Studies, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 17 - Partnerships for the Goals, Microbiome Announcement, RNA, Ribosomal, 16S, WIDE ASSOCIATION, Humans, Microbiome, Genome-wide association studies (GWAS), GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Genetic association, Gut microbiome, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, Bacteria, Genome, Human, Gastrointestinal Microbiome, Human microbiome, Genetic Variation, biology.organism_classification, 3. Good health, Meta-analysis, 030104 developmental biology, Research Programm of Donders Centre for Neuroscience, lcsh:QR100-130, Human genome, Genome-Wide Association Study
Abstract: Background In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed. Electronic supplementary material The online version of this article (10.1186/s40168-018-0479-3) contains supplementary material, which is available to authorized users.
Published: 2018
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46. Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes

Author: Jenifer J. Ware, Michelle Taylor, Pekka Jousilahti, Dorret I. Boomsma, Richard Sherva, Laura J. Bierut, Camelia C. Minică, Kenneth S. Kendler, Hermine H. Maes, Caryn Lerman, Rachel F. Tyndale, John E. Hokanson, Henry R. Kranzler, Michael M. Vanyukov, Ming D. Li, Gonneke Willemsen, Jaakko Kaprio, Peilin Jia, Joel Gelernter, Fangyi Gu, Brion S. Maher, Pamela A. F. Madden, Zhongming Zhao, Neil E. Caporaso, Anu Loukola, Jacqueline M. Vink, D. M. Dick, Xiangning Chen, Nathan C. Gaddis, Nathan A. Gillespie, Brien P. Riley, Jingchun Chen, Maria Teresa Landi, Dana B. Hancock, Eric O. Johnson, Beenish Qaiser, Jenni Hällfors, Michael F. Miles, Lindsay A. Farrer, Timothy B. Baker, Sharon M. Lutz, Roseann E. Peterson, M. Imad Damaj, Tellervo Korhonen, Marcus R. Munafò, Meghan J. Chenoweth, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, and APH - Methodology
Subjects: Receptor recycling, Fagerstrom Test for Nicotine Dependence, Netherlands Twin Register (NTR), Genetic Markers, media_common.quotation_subject, Original Investigations, RBFOX1, Biology, Brain and Behaviour, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cigarette Smoking, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, mental disorders, Humans, Genetic Predisposition to Disease, Gene, 030304 developmental biology, media_common, Genetics, 0303 health sciences, Genome, Human, Addiction, Tobacco and Alcohol, Public Health, Environmental and Occupational Health, Tobacco Use Disorder, Actin cytoskeleton, Phenotype, Genetic architecture, United States, 3. Good health, Reelin Protein, Physical and Mental Health, Developmental Psychopathology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. Conclusions Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. Implications Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.
Published: 2018
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47. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

Author: Dorret I. Boomsma, Søren Brunak, Adem Y. Dawed, Gonneke Willemsen, Mark I. McCarthy, Martijn van de Bunt, Karina Banasik, Leen M 't Hart, Valborg Gudmundsdottir, Mark H. H. Kramer, Jorge Ferrer, Eco J. C. de Geus, Axel Dietrich, Caroline Brorsson, Ramneek Gupta, A.M.C. Simonis-Bik, Anubha Mahajan, Elisabeth M. W. Eekhoff, Hans-Ulrich Häring, Thomas Hübschle, Christopher J. Groves, Andreas Fritsche, Harald Staiger, Joris Deelen, Karla V. Allebrandt, Helle Krogh Pedersen, Nienke van Leeuwen, Ewan R. Pearson, Internal medicine, ACS - Diabetes & metabolism, AII - Inflammatory diseases, Division 6, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, and APH - Personalized Medicine
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Proteomics, Physiology, medicine.medical_treatment, Gene Identification and Analysis, lcsh:Medicine, Adipose tissue, Gene Expression, White adipose tissue, Genetic Networks, Biochemistry, Mice, Endocrinology, Glucagon-Like Peptide 1/metabolism, Glucagon-Like Peptide 1, Insulin Secretion, Medicine and Health Sciences, Insulin, lcsh:Science, Receptor, Regulation of gene expression, Multidisciplinary, Genomics, Adipose Tissue, Protein Interaction Networks, Anatomy, Network Analysis, medicine.drug, Research Article, medicine.medical_specialty, Computer and Information Sciences, General Science & Technology, Context (language use), Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Gene Types, Internal medicine, MD Multidisciplinary, Journal Article, medicine, Genetics, Genome-Wide Association Studies, Animals, Humans, Gene Regulation, Insulin/secretion, Endocrine Physiology, Liraglutide, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Actin cytoskeleton, Genome Analysis, 030104 developmental biology, Biological Tissue, Regulator Genes, lcsh:Q
Abstract: Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
Published: 2018
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48. Selective maternal seeding and environment shape the human gut microbiome

Author: Nicola Segata, Gonneke Willemsen, Stefanie Kandels-Lewis, Katri Korpela, Paul I. Costea, Luis Pedro Coelho, Dorret I. Boomsma, Peer Bork, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Research Programs Unit, Immunobiology Research Program, Medicum, Department of Bacteriology and Immunology, and University of Helsinki
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Bacteroidia, TRANSMISSION, DIVERSITY, Clostridiaceae, Mothers, BIFIDOBACTERIA, Polymorphism, Single Nucleotide, METAGENOMICS, MATURATION, Actinobacteria, Feces, DELIVERY, 03 medical and health sciences, Pregnancy, RNA, Ribosomal, 16S, REVEALS, Genetics, medicine, Humans, Colonization, Microbiome, Genetics (clinical), 2. Zero hunger, Maternal Transmission, biology, Bacteroidetes, Transmission (medicine), Research, Microbiota, Infant, Newborn, biology.organism_classification, medicine.disease, Mother-Child Relations, Gastrointestinal Microbiome, 030104 developmental biology, Cardiovascular and Metabolic Diseases, BACTERIA, Female, INFANT, HEALTH, 3111 Biomedicine
Abstract: Vertical transmission of bacteria from mother to infant at birth is postulated to initiate a life-long host-microbe symbiosis, playing an important role in early infant development. However, only the tracking of strictly defined unique microbial strains can clarify where the intestinal bacteria come from, how long the initial colonizers persist, and whether colonization by other strains from the environment can replace existing ones. Using rare single nucleotide variants in fecal metagenomes of infants and their family members, we show strong evidence of selective and persistent transmission of maternal strain populations to the vaginally born infant and their occasional replacement by strains from the environment, including those from family members, in later childhood. Only strains from the classes Actinobacteria and Bacteroidia, which are essential components of the infant microbiome, are transmitted from the mother and persist for at least 1 yr. In contrast, maternal strains of Clostridia, a dominant class in the mother's gut microbiome, are not observed in the infant. Caesarean-born infants show a striking lack of maternal transmission at birth. After the first year, strain influx from the family environment occurs and continues even in adulthood. Fathers appear to be more frequently donors of novel strains to other family members than receivers. Thus, the infant gut is seeded by selected maternal bacteria, which expand to form a stable community, with a rare but stable continuing strain influx over time.
Published: 2018
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49. Metataxonomic Analysis of Individuals at BMI Extremes and Monozygotic Twins Discordant for BMI

Author: Gonneke Willemsen, Conor V. Dolan, Justin M. Luningham, Gareth E. Davies, Erik A. Ehli, Dorret I. Boomsma, Jeffrey J. Beck, Casey T. Finnicum, Richard G. IJzerman, Stieneke Doornweerd, Eco J. C. de Geus, Internal medicine, VU University medical center, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Biological Psychology, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, and APH - Personalized Medicine
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Adult, Male, obesity, 030106 microbiology, Biology, Gut flora, digestive system, Body Mass Index, 03 medical and health sciences, Human gut, SDG 3 - Good Health and Well-being, Oxalobacteraceae, Ruminococcus, medicine, Humans, Genetic risk, Genetics (clinical), Genetics, Discordant Twin, gut microbiota, Obstetrics and Gynecology, twins, Twins, Monozygotic, biology.organism_classification, medicine.disease, Phenotype, Obesity, Gastrointestinal Microbiome, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Alpha diversity, Female, Ruminococcaceae
Abstract: Objective: The human gut microbiota has been demonstrated to be associated with a number of host phenotypes, including obesity and a number of obesity-associated phenotypes. This study is aimed at further understanding and describing the relationship between the gut microbiota and obesity-associated measurements obtained from human participants. Subjects/Methods: Here, we utilize genetically informative study designs, including a four-corners design (extremes of genetic risk for BMI and of observed BMI; N = 50) and the BMI monozygotic (MZ) discordant twin pair design (N = 30), in order to help delineate the role of host genetics and the gut microbiota in the development of obesity. Results: Our results highlight a negative association between BMI and alpha diversity of the gut microbiota. The low genetic risk/high BMI group of individuals had a lower gut microbiota alpha diversity when compared to the other three groups. Although the difference in alpha diversity between the lean and heavy groups of the BMI-discordant MZ twin design did not achieve significance, this difference was observed to be in the expected direction, with the heavier participants having a lower average alpha diversity. We have also identified nine OTUs observed to be associated with either a leaner or heavier phenotype, with enrichment for OTUs classified to the Ruminococcaceae and Oxalobacteraceae taxonomic families. Conclusion: Our study presents evidence of a relationship between BMI and alpha diversity of the gut microbiota. In addition to these findings, a number of OTUs were found to be significantly associated with host BMI. These findings may highlight separate subtypes of obesity, one driven by genetic factors, the other more heavily influenced by environmental factors.
Published: 2018
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50. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018
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