Author: "Delilah Zabaneh" - Searchworks@Jio Institute Digital Library Search Results

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1. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author: Ilja M. Nolte, M. Loretto Munoz, Vinicius Tragante, Azmeraw T. Amare, Rick Jansen, Ahmad Vaez, Benedikt von der Heyde, Christy L. Avery, Joshua C. Bis, Bram Dierckx, Jenny van Dongen, Stephanie M. Gogarten, Philippe Goyette, Jussi Hernesniemi, Ville Huikari, Shih-Jen Hwang, Deepali Jaju, Kathleen F. Kerr, Alexander Kluttig, Bouwe P. Krijthe, Jitender Kumar, Sander W. van der Laan, Leo-Pekka Lyytikäinen, Adam X. Maihofer, Arpi Minassian, Peter J. van der Most, Martina Müller-Nurasyid, Michel Nivard, Erika Salvi, James D. Stewart, Julian F. Thayer, Niek Verweij, Andrew Wong, Delilah Zabaneh, Mohammad H. Zafarmand, Abdel Abdellaoui, Sulayma Albarwani, Christine Albert, Alvaro Alonso, Foram Ashar, Juha Auvinen, Tomas Axelsson, Dewleen G. Baker, Paul I. W. de Bakker, Matteo Barcella, Riad Bayoumi, Rob J. Bieringa, Dorret Boomsma, Gabrielle Boucher, Annie R. Britton, Ingrid Christophersen, Andrea Dietrich, George B. Ehret, Patrick T. Ellinor, Markku Eskola, Janine F. Felix, John S. Floras, Oscar H. Franco, Peter Friberg, Maaike G. J. Gademan, Mark A. Geyer, Vilmantas Giedraitis, Catharina A. Hartman, Daiane Hemerich, Albert Hofman, Jouke-Jan Hottenga, Heikki Huikuri, Nina Hutri-Kähönen, Xavier Jouven, Juhani Junttila, Markus Juonala, Antti M. Kiviniemi, Jan A. Kors, Meena Kumari, Tatiana Kuznetsova, Cathy C. Laurie, Joop D. Lefrandt, Yong Li, Yun Li, Duanping Liao, Marian C. Limacher, Henry J. Lin, Cecilia M. Lindgren, Steven A. Lubitz, Anubha Mahajan, Barbara McKnight, Henriette Meyer zu Schwabedissen, Yuri Milaneschi, Nina Mononen, Andrew P. Morris, Mike A. Nalls, Gerjan Navis, Melanie Neijts, Kjell Nikus, Kari E. North, Daniel T. O'Connor, Johan Ormel, Siegfried Perz, Annette Peters, Bruce M. Psaty, Olli T. Raitakari, Victoria B. Risbrough, Moritz F. Sinner, David Siscovick, Johannes H. Smit, Nicholas L. Smith, Elsayed Z. Soliman, Nona Sotoodehnia, Jan A. Staessen, Phyllis K. Stein, Adrienne M. Stilp, Katarzyna Stolarz-Skrzypek, Konstantin Strauch, Johan Sundström, Cees A. Swenne, Ann-Christine Syvänen, Jean-Claude Tardif, Kent D. Taylor, Alexander Teumer, Timothy A. Thornton, Lesley E. Tinker, André G. Uitterlinden, Jessica van Setten, Andreas Voss, Melanie Waldenberger, Kirk C. Wilhelmsen, Gonneke Willemsen, Quenna Wong, Zhu-Ming Zhang, Alan B. Zonderman, Daniele Cusi, Michele K. Evans, Halina K. Greiser, Pim van der Harst, Mohammad Hassan, Erik Ingelsson, Marjo-Riitta Järvelin, Stefan Kääb, Mika Kähönen, Mika Kivimaki, Charles Kooperberg, Diana Kuh, Terho Lehtimäki, Lars Lind, Caroline M. Nievergelt, Chris J. O'Donnell, Albertine J. Oldehinkel, Brenda Penninx, Alexander P. Reiner, Harriëtte Riese, Arie M. van Roon, John D. Rioux, Jerome I. Rotter, Tamar Sofer, Bruno H. Stricker, Henning Tiemeier, Tanja G. M. Vrijkotte, Folkert W. Asselbergs, Bianca J. J. M. Brundel, Susan R. Heckbert, Eric A. Whitsel, Marcel den Hoed, Harold Snieder, and Eco J. C. de Geus
Subjects: Science
Abstract: Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.
Published: 2017
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2. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author: Ilja M. Nolte, M. Loretto Munoz, Vinicius Tragante, Azmeraw T. Amare, Rick Jansen, Ahmad Vaez, Benedikt von der Heyde, Christy L. Avery, Joshua C. Bis, Bram Dierckx, Jenny van Dongen, Stephanie M. Gogarten, Philippe Goyette, Jussi Hernesniemi, Ville Huikari, Shih-Jen Hwang, Deepali Jaju, Kathleen F. Kerr, Alexander Kluttig, Bouwe P. Krijthe, Jitender Kumar, Sander W. van der Laan, Leo-Pekka Lyytikäinen, Adam X. Maihofer, Arpi Minassian, Peter J. van der Most, Martina Müller-Nurasyid, Michel Nivard, Erika Salvi, James D. Stewart, Julian F. Thayer, Niek Verweij, Andrew Wong, Delilah Zabaneh, Mohammad H. Zafarmand, Abdel Abdellaoui, Sulayma Albarwani, Christine Albert, Alvaro Alonso, Foram Ashar, Juha Auvinen, Tomas Axelsson, Dewleen G. Baker, Paul I. W. de Bakker, Matteo Barcella, Riad Bayoumi, Rob J. Bieringa, Dorret Boomsma, Gabrielle Boucher, Annie R. Britton, Ingrid Christophersen, Andrea Dietrich, George B. Ehret, Patrick T. Ellinor, Markku Eskola, Janine F. Felix, John S. Floras, Oscar H. Franco, Peter Friberg, Maaike G. J. Gademan, Mark A. Geyer, Vilmantas Giedraitis, Catharina A. Hartman, Daiane Hemerich, Albert Hofman, Jouke-Jan Hottenga, Heikki Huikuri, Nina Hutri-Kähönen, Xavier Jouven, Juhani Junttila, Markus Juonala, Antti M. Kiviniemi, Jan A. Kors, Meena Kumari, Tatiana Kuznetsova, Cathy C. Laurie, Joop D. Lefrandt, Yong Li, Yun Li, Duanping Liao, Marian C. Limacher, Henry J. Lin, Cecilia M. Lindgren, Steven A. Lubitz, Anubha Mahajan, Barbara McKnight, Henriette Meyer zu Schwabedissen, Yuri Milaneschi, Nina Mononen, Andrew P. Morris, Mike A. Nalls, Gerjan Navis, Melanie Neijts, Kjell Nikus, Kari E. North, Daniel T. O'Connor, Johan Ormel, Siegfried Perz, Annette Peters, Bruce M. Psaty, Olli T. Raitakari, Victoria B. Risbrough, Moritz F. Sinner, David Siscovick, Johannes H. Smit, Nicholas L. Smith, Elsayed Z. Soliman, Nona Sotoodehnia, Jan A. Staessen, Phyllis K. Stein, Adrienne M. Stilp, Katarzyna Stolarz-Skrzypek, Konstantin Strauch, Johan Sundström, Cees A. Swenne, Ann-Christine Syvänen, Jean-Claude Tardif, Kent D. Taylor, Alexander Teumer, Timothy A. Thornton, Lesley E. Tinker, André G. Uitterlinden, Jessica van Setten, Andreas Voss, Melanie Waldenberger, Kirk C. Wilhelmsen, Gonneke Willemsen, Quenna Wong, Zhu-Ming Zhang, Alan B Zonderman, Daniele Cusi, Michele K. Evans, Halina K. Greiser, Pim van der Harst, Mohammad Hassan, Erik Ingelsson, Marjo-Riitta Järvelin, Stefan Kääb, Mika Kähönen, Mika Kivimaki, Charles Kooperberg, Diana Kuh, Terho Lehtimäki, Lars Lind, Caroline M. Nievergelt, Chris J. O'Donnell, Albertine J. Oldehinkel, Brenda Penninx, Alexander P. Reiner, Harriëtte Riese, Arie M. van Roon, John D. Rioux, Jerome I. Rotter, Tamar Sofer, Bruno H. Stricker, Henning Tiemeier, Tanja G. M. Vrijkotte, Folkert W. Asselbergs, Bianca J. J.M Brundel, Susan R. Heckbert, Eric A. Whitsel, Marcel den Hoed, Harold Snieder, and Eco J. C. de Geus
Subjects: Science
Abstract: Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.
Published: 2017
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3. Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Author: Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom Gaunt, Michael V Holmes, Helen Warren, Daniel I Swerdlow, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Reecha Sofat, Mark Caulfield, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia Langenberg, Yoav Ben-Shlomo, Ian N Day, Peter Whincup, Richard Morris, Mark W J Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, Frank Dudbridge, John C Whittaker, Juan P Casas, Aroon D Hingorani, and UCLEB Consortium
Subjects: Medicine, Science
Abstract: Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
Published: 2013
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4. Correction: Population Genomics of Cardiometabolic Traits: Design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Author: Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom Gaunt, Michael V. Holmes, Helen Warren, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Reecha Sofat, Mark Caulfield, Shah Ebrahim, Debbie A. Lawlor, Philippa J. Talmud, Steve E. Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Yoav Ben-Shlomo, Ian N. Day, Peter Whincup, Richard Morris, Mark W. J. Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, Frank Dudbridge, John C. Whittaker, Juan P. Casas, and Aroon D. Hingorani
Subjects: Medicine, Science
Published: 2013
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5. A genome-wide association study of the metabolic syndrome in Indian Asian men.

Author: Delilah Zabaneh and David J Balding
Subjects: Medicine, Science
Abstract: We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits: HDL-cholesterol, plasma glucose and Type 2 diabetes, abdominal obesity measured by waist to hip ratio, and diastolic blood pressure. Association was tested with these four traits and a composite metabolic syndrome phenotype. Four SNPs reaching significance level p0.8 were found in genes CETP and LPL, associated with HDL-cholesterol. These associations have already been reported in Indian Asians and in Europeans. Five additional loci harboured SNPs significant at p0.5 for HDL-cholesterol, type 2 diabetes or diastolic blood pressure. Our results suggest that the primary genetic determinants of metabolic syndrome are the same in Indian Asians as in other populations, despite the higher prevalence. Further, we found little evidence of a common genetic basis for metabolic syndrome traits in our sample of Indian Asian men.
Published: 2010
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6. HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics.

Author: Jie Zheng 0006, Santiago Rodríguez, Charles Laurin, Denis Baird, Lea Trela-Larsen, Mesut A. Erzurumluoglu, Yi Zheng, Jon White, Claudia Giambartolomei, Delilah Zabaneh, Richard Morris, Meena Kumari, Juan P. Casas, Aroon D. Hingorani, David M. Evans 0002, Tom R. Gaunt, and Ian N. M. Day
Published: 2017
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7. 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

8. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author: Dan Rujescu, Vidar M. Steen, Eva Krapohl, Aarno Palotie, Elisabeth Widen, Ingrid Melle, Patrick Sullivan, Katrina L. Grasby, Stephan Ripke, Anke R. Hammerschlag, Christiaan de Leeuw, Panos Bitsios, Nikos C. Stefanis, Tonya White, Gail Davies, Ahmad R. Hariri, Philip R. Jansen, Peter B. Barr, John M. Starr, Max Lam, Ian J. Deary, Sara Hägg, Dimitrios Avramopoulos, Bettina Konte, Anil K. Malhotra, Delilah Zabaneh, Kjetil Sundet, Tinca J. C. Polderman, Ornit Chiba-Falek, Jakob Kaminski, Danielle M. Dick, Andrea Christoforou, Jin Yu, Gunter Schumann, Matthew A. Scult, Anna C. Need, Jens Hjerling-Leffler, Gonçalo R. Abecasis, Kenneth S. Kendler, Todd Lencz, Dwight Dickinson, Bradley T. Webb, Elizabeth T. Cirulli, Stephanie Le Hellard, Gerome Breen, Astri J. Lundervold, Hannah Young, Erin Burke Quinlan, William Ollier, Nikolaos Smyrnis, Emily Drabant Conley, Danielle Posthuma, Sten Linnarsson, Aristotle N. Voineskos, Edythe D. London, Pamela DeRosse, Russell A. Poldrack, Jonathan R. I. Coleman, Jeanne E. Savage, Sarah E. Medland, Ana B. Muñoz-Manchado, Richard E. Straub, Robert Plomin, Ida K. Karlsson, Nathan G. Skene, Dan E. Arking, Birgit Debrabant, Joey W. Trampush, Matthew C. Keller, Mats Nagel, Gary Donohoe, Chandra A. Reynolds, Panos Roussos, Lene Christiansen, Ivar Reinvang, Ole A. Andreassen, Antony Payton, Robert Karlsson, Margaret J. Wright, Deborah C. Koltai, Jari Lahti, Andreas Heinz, Tyrone D. Cannon, Eliza Congdon, Olav B. Smeland, Stella G. Giakoumaki, Marianne Nygaard, Julien Bryois, M. Arfan Ikram, Nancy L. Pedersen, Katri Räikkönen, Daniel R. Weinberger, Neil Pendleton, Swapnil Awasthi, Sven Stringer, Nelson A. Freimer, Aiden Corvin, Kyoko Watanabe, David C. Glahn, Henning Tiemeier, Grant W. Montgomery, Narelle K. Hansell, Robert M. Bilder, Katherine E. Burdick, Srdjan Djurovic, David C. Liewald, Sophie van der Sluis, Thomas Espeseth, Scott I. Vrieze, Fred W. Sabb, Nicholas G. Martin, Michael Gill, Emma Knowles, Derek W. Morris, Alex Hatzimanolis, Ina Giegling, Johan G. Eriksson, Child and Adolescent Psychiatry / Psychology, Epidemiology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, Functional Genomics, Research Programs Unit, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, Johan Eriksson / Principal Investigator, Clinicum, University of Helsinki, Medicum, Helsinki Collegium for Advanced Studies, Department of Psychology and Logopedics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Elisabeth Ingrid Maria Widen / Principal Investigator, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, VU University medical center, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Nonsynonymous substitution, Male, GENERAL COGNITIVE FUNCTION, Intelligence, LOCI, Genome-wide association study, ANNOTATION, 0302 clinical medicine, GWAS, 11 Medical and Health Sciences, Genetics & Heredity, RISK, HERITABILITY, Brain, Mendelian Randomization Analysis, Middle Aged, 3. Good health, Schizophrenia, Genome-Wide Association Study/methods, Female, Life Sciences & Biomedicine, TRAITS, Adolescent, Quantitative Trait Loci, Computational biology, Biology, Quantitative trait locus, Brain/physiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetic association, EDUCATIONAL-ATTAINMENT, Science & Technology, TEST BATTERIES, CONSORTIUM, Intelligence/genetics, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Expression quantitative trait loci, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Published: 2018

9. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Author: Gerome Breen, Suzanne Sniekers, Neil Pendleton, Robert Plomin, Antony Payton, Magnus Johannesson, Anke R. Hammerschlag, Sven Stringer, Philipp Koellinger, Matt McGue, David Cesarini, Najaf Amin, Christopher F. Chabris, Delilah Zabaneh, Cornelia M. van Duijn, Cornelius A. Rietveld, Aysu Okbay, Jonathan R. I. Coleman, Michael B. Miller, Danielle Posthuma, Eva Krapohl, Erdogan Taskesen, William G. Iacono, Kyoko Watanabe, Philip R. Jansen, Patrik K. E. Magnusson, William E R Ollier, James J. Lee, Henning Tiemeier, M. Arfan Ikram, Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Child and Adolescent Psychiatry / Psychology, Applied Economics, Epidemiology, Psychiatry, Mathematics, Complex Trait Genetics, Tinbergen Institute, Graduate School, and Human Genetics
Subjects: 0301 basic medicine, Adult, Male, Linkage disequilibrium, Adolescent, European Continental Ancestry Group, Intelligence, Single-nucleotide polymorphism, Genome-wide association study, Nerve Tissue Proteins, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Article, White People, Linkage Disequilibrium, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetics, Journal Article, Brain/metabolism, Nerve Tissue Proteins/genetics, Humans, Polymorphism, Child, Preschool, Gene, Aged, Human intelligence, Research, Intelligence/genetics, Brain, Infant, Single Nucleotide, Heritability, Middle Aged, Genetic architecture, 030104 developmental biology, Child, Preschool, Female, 030217 neurology & neurosurgery, White People/genetics, Genome-Wide Association Study, Meta-Analysis
Abstract: Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta- A nalysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.
Published: 2017

10. HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics

Author: Lea Trela-Larsen, Yi Zheng, Jie Zheng, Meena Kumari, Aroon D. Hingorani, Richard W Morris, Claudia Giambartolomei, A. Mesut Erzurumluoglu, Delilah Zabaneh, Denis Baird, Jon White, Charles Laurin, David M. Evans, Ian N. M. Day, Tom R. Gaunt, Santiago Rodriguez, and Juan P. Casas
Subjects: 0301 basic medicine, Statistics and Probability, medicine.medical_specialty, Genotype, Computer science, Iterative method, Genome-wide association study, 030105 genetics & heredity, computer.software_genre, Biochemistry, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Unit (housing), 03 medical and health sciences, Quantitative Trait, Heritable, Gene Frequency, Epidemiology, medicine, Humans, Molecular Biology, Haplotype, Chromosome Mapping, Data science, Summary statistics, Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, Haplotypes, Sample Size, Data mining, computer, Software, Genome-Wide Association Study
Abstract: Motivation Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2) of the variants. However, haplotypes rather than pairwise r2, are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N Availability and Implementation The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2016

11. Cystatin C and Cardiovascular Disease

Author: Heribert Schunkert, Wolfgang Koenig, Jessica van Setten, Meena Kumari, Johan Ärnlöv, J. Wouter Jukema, Vinicius Tragante, Alanna C. Morrison, Bradford B. Worrall, Brendan J. Keating, Alexander Teumer, Vilmantas Giedraitis, Tom Wilsgaard, Nilesh J. Samani, Barbara Thorand, Patricia B. Munroe, Rainer Malik, Melanie Waldenberger, Christopher P. Nelson, Sebastian E. Baumeister, Aroon D. Hingorani, Stéphanie Debette, Tove Fall, Patrik K. E. Magnusson, Nora Franceschini, Anders Larsson, Andrew P. Morris, Folkert W. Asselbergs, Maryam Kavousi, Oscar H. Franco, Jeanette Erdmann, Jonathan Marchini, Mika Kivimäki, Ivana Išgum, Fotios Drenos, N. Charlotte Onland-Moret, Bjørn Odvar Eriksen, Aicha Soumare, Christopher J. O'Donnell, Ingrid Toft, Paul I.W. de Bakker, Johannes Arpegård, Jacqueline de Graaf, Abbas Dehghan, Delilah Zabaneh, Michael V. Holmes, Yvonne T. van der Schouw, Alexander P. Reiner, André G. Uitterlinden, Christa Meisinger, Janine F. Felix, Erik Ingelsson, Lars Lind, Martin Dichgans, Marcus Dörr, Albert Hofman, Sanaz Sedaghat, Lambertus A. Kiemeney, Joshua C. Bis, Jens Baumert, Tessel E. Galesloot, Hester M. den Ruijter, Gerard Pasterkamp, Annette Peters, Naveed Sattar, Nancy L. Pedersen, Pim van der Harst, Stella Trompet, Per Svensson, Riyaz S. Patel, Philippe Amouyel, and Sander W. van der Laan
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Population, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, medicine, education, education.field_of_study, biology, business.industry, Confounding, Mendelian Randomization Analysis, 3. Good health, Minor allele frequency, 030104 developmental biology, Cystatin C, biology.protein, Cystatin, Cardiology and Cardiovascular Medicine, business
Abstract: BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.
Published: 2016

12. Assessing potential shared genetic aetiology between body mass index and sleep duration in 142,209 individuals

Author: Victoria, Garfield, Ghazaleh, Fatemifar, Caroline, Dale, Melissa, Smart, Yanchun, Bao, Clare H, Llewellyn, Andrew, Steptoe, Delilah, Zabaneh, and Meena, Kumari
Subjects: Adult, Male, Multifactorial Inheritance, Time Factors, body mass index, Middle Aged, genetic correlation, Phenotype, polygenic risk score, Humans, sleep duration, Female, Obesity, Self Report, Sleep, Genetic Association Studies, Research Articles, Aged, Research Article
Abstract: Observational studies find an association between increased body mass index (BMI) and short self‐reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self‐reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self‐reported sleep duration in a combination of individual participant data and summary‐level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (r g = −0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = −1.75 min [SE = 0.67], P = 6.13 × 10−7), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self‐reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations.
Published: 2018

13. A genome-wide association study for extremely high intelligence

Author: Gerome Breen, Robert Plomin, H M Wu, Eva Krapohl, Delilah Zabaneh, Helena Gaspar, Martha Putallaz, Charles Curtis, Hamel Patel, Sang Hyuck Lee, Stephen Newhouse, David Lubinski, Michael A. Simpson, Zabaneh, D, Krapohl, E, Gaspar, HA, Curtis, C, Lee, Sang Hong, Patel, H, Newhouse, S, Wu, HM, Simpson, MA, Putallaz, M, Lubinski, D, Plomin, R, and Breen, G
Subjects: Adult, Male, 0301 basic medicine, Multifactorial Inheritance, Adolescent, Intelligence, Population, ADAM12 Protein, Locus (genetics), Genome-wide association study, Quantitative trait locus, high intelligence, Polymorphism, Single Nucleotide, genetic study, 03 medical and health sciences, Cellular and Molecular Neuroscience, Quantitative Trait, Heritable, genome-wide association (GWA), Humans, Longitudinal Studies, education, Molecular Biology, Genetics, education.field_of_study, Heritability, Explained variation, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Sample size determination, Case-Control Studies, educational attainment, Trait, Original Article, Female, Psychology, Genome-Wide Association Study, Clinical psychology
Abstract: We used a case-control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (∼170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population. usc Refereed/Peer-reviewed
Published: 2018

14. Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations

Author: Meena Kumari, John R. B. Perry, Jian'an Luan, Robert A. Scott, Delilah Zabaneh, Michaela Benzeval, Eleftheria Zeggini, Claudia Langenberg, Nicholas J. Wareham, Karoline Kuchenbaecker, Melissa C. Smart, Bram P. Prins, Ghazaleh Fatemifar, Yanchun Bao, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Perry, John [0000-0001-6483-3771], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Genetic Markers, Longitudinal study, Health Status, lcsh:Medicine, Genome-wide association study, Article, 03 medical and health sciences, Liver disease, medicine, Longitudinal Studies, 1000 Genomes Project, lcsh:Science, Genetics, Family Health, Family Characteristics, Multidisciplinary, biology, Haplotype, lcsh:R, medicine.disease, Genetic architecture, United Kingdom, 3. Good health, 030104 developmental biology, Reproductive Health, Alanine transaminase, biology.protein, Biomarker (medicine), lcsh:Q, Biomarkers, Genome-Wide Association Study
Abstract: Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 × 10−10) was associated with levels of alanine transaminase, an indicator of liver damage. The variant is located in the gene encoding serine protease inhibitor, low levels of which are associated with alpha-1 antitrypsin deficiency which leads to liver disease. We identified novel associations (rs78900934, beta = 0.05, P = 6 × 10−12; rs2911280, beta = 0.09, P = 6 × 10−10) for dihydroepiandrosterone sulphate, a precursor to major sex-hormones, and for glycated haemoglobin (rs12819124, beta = −0.03, P = 4 × 10−9; rs761772, beta = 0.05, P = 5 × 10−9). rs12819124 is nominally associated with risk of type 2 diabetes. Our study offers insights into the genetic architecture of well-known and less well-studied biomarkers.
Published: 2017

15. Low levels of IgM antibodies against phosphorylcholine are associated with fast carotid intima media thickness progression and cardiovascular risk in men

Author: Elena Tremoli, Delilah Zabaneh, Max Vikström, Karin Leander, Karl Gertow, Philippe Giral, Johan Frostegård, Olga McLeod, Damiano Baldassarre, Rona J. Strawbridge, Fabrizio Veglia, Steve E. Humphries, Rainer Rauramaa, Ulf de Faire, Sonia Shah, Andries J. Smit, Anders Hamsten, Jussi Kauhanen, Bengt Sennblad, Elmo Mannarino, Bruna Gigante, Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)
Subjects: Carotid Artery Diseases, Male, Percentile, PREDICTOR, Logistic regression, Autoantigens, Carotid Intima-Media Thickness, Antibody Specificity, Carotid intima media thickness, TROMSO, Myocardial infarction, Sex Characteristics, Anthropometry, Incidence (epidemiology), Age Factors, WOMEN, NATURAL ANTIBODIES, Middle Aged, Cardiovascular disease, Europe, Quartile, Cardiovascular Diseases, Cardiology, Antibodies, Antiphospholipid, Disease Progression, Biomarker (medicine), Female, Anti-PC, Cardiology and Cardiovascular Medicine, Carotid intima media thickness progression, medicine.medical_specialty, IMPROVE, Phosphorylcholine, Cardiovascular events, Internal medicine, medicine, Humans, Subclinical atherosclerosis, EUROPEAN POPULATION, Aged, Proportional Hazards Models, VASCULAR EVENTS, Proportional hazards model, business.industry, Biomarker, medicine.disease, Surgery, Intima-media thickness, Immunoglobulin M, Risk factors, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, business, PROTECTIVE FACTORS, Follow-Up Studies
Abstract: Objective: Low levels of IgM anti-phosphorylcholine (anti-PC) increase the risk of cardiovascular events (CVE). Here we investigate the association of low anti-PC with the progression of carotid intima media thickness (C-IMT) and incidence of CVE in a large cohort of individuals at high risk of CVE, the IMPROVE, a prospective multicenter European study.Methods: 3711 subjects (54-79 years) with at least three established cardiovascular risk factors were enrolled. Baseline serum levels of IgM anti-PC were measured by ELISA. Carotid ultrasound investigations were performed at baseline and after 15 and 30 months of follow-up. The risk of C-IMT progression and ischemic CVE associated with low anti-PC levels was tested by logistic regression and Cox regression analysis, respectively. Risk estimates were adjusted by center and conventional cardiovascular risk factors.Results: 3670 study participants were included in the present analysis and 213 CVE were recorded during a 3 year follow up. Anti-PC levels (U/ml) were classified into quartiles [Q1 40-64- 102]. In men, low levels of anti-PC (Q1) were associated with the highest (> 90th) percentile of the fastest C-IMT progression, i.e. the segment showing the fastest progression over 30 months in the whole carotid tree, with an OR of 1.41 (95%CI, 1.02-1.9) and with an increased risk of CVE with a multivariable adjusted HR of 1.85 (95%CI, 1.1-3.1). No significant associations were found in women.Conclusions: Low anti-PC levels increase the risk of CVE in men. This effect may be partly mediated by a fast C-IMT progression. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
Published: 2014

16. Erratum: Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Author: Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn, Danielle Posthuma, Clinical genetics, NCA - Brain mechanisms in health and disease, VU University medical center, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Psychiatry
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetics, Journal Article, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2017

17. GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Author: Lene Christiansen, Robert M. Bilder, Katherine E. Burdick, Tinca J. C. Polderman, Ana B. Muñoz-Manchado, Gary Donohoe, Matthew C. Keller, Stephan Ripke, Anil K. Malhotra, Delilah Zabaneh, Andrea Christoforou, Matthew A. Scult, Nikolaos Smyrnis, Scott I. Vrieze, Fred W. Sabb, Stella G. Giakoumaki, Nathan G. Skene, Ole A. Andreassen, Nicholas G. Martin, Jari Lahti, Anna C. Need, Philip R. Jansen, Todd Lencz, Emma Knowles, Peter B. Barr, Pamela DeRosse, Russell A. Poldrack, Henning Tiemeier, Sten Linnarsson, Hannah Young, Emily Drabant Conley, Dan E. Arking, Jin Yu, Grant W. Montgomery, Danielle Posthuma, Dwight Dickinson, Elizabeth T. Cirulli, Gerome Breen, Gunter Schumann, Michael Gill, Erin Burke Quinlan, Robert Plomin, Kyoko Watanabe, Joey W. Trampush, John M. Starr, Katri Räikkönen, Narelle K. Hansell, Eliza Congdon, Olav B. Smeland, Jens Hjerling-Leffler, Richard E. Straub, Aiden Corvin, Chandra A. Reynolds, Astri J. Lundervold, Bradley T. Webb, Gonçalo R. Abecasis, Jonathan R. I. Coleman, Srdjan Djurovic, Margaret J. Wright, Kjetil Sundet, Ivar Reinvang, Robert Karlsson, Deborah C. Koltai, Ina Giegling, Alex Hatzimanolis, David C. Liewald, William Ollier, Sophie van der Sluis, Edythe D. London, Tyrone D. Cannon, Thomas Espeseth, M. Arfan Ikram, Ian J. Deary, Christiaan de Leeuw, Daniel R. Weinberger, Neil Pendleton, Ornit Chiba-Falek, Jakob Kaminski, Danielle M. Dick, Panos Bitsios, Nikos C. Stefanis, Tonya White, Bettina Konte, Ida K. Karlsson, Mats Nagel, Derek W. Morris, Anke R. Hammerschlag, Swapnil Awasthi, Antony Payton, Julien Bryois, Nelson A. Freimer, Nancy L. Pedersen, Panos Roussos, Andreas Heinz, Johan G. Eriksson, Marianne Nygaard, Birgit Debrabant, Aarno Palotie, Elisabeth Widen, Aristotle N. Voineskos, Patrick Sullivan, Ingrid Melle, Dan Rujescu, Vidar M. Steen, Eva Krapohl, Katrina L. Grasby, Max Lam, Stephanie Le Hellard, Kenneth S. Kendler, Jeanne E. Savage, Sarah E. Medland, Sven Stringer, David C. Glahn, Gail Davies, Ahmad R. Hariri, Sara Hägg, and Dimitrios Avramopoulos
Subjects: Genetics, Nonsynonymous substitution, 0303 health sciences, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy, Mendelian randomization, Expression quantitative trait loci, Neuron differentiation, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence3–7, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimer’s dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.
Published: 2017
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18. Erratum

Author: Deepali Jaju, Melanie Neijts, Gabrielle Boucher, Arpi Minassian, James D. Stewart, Andreas Voss, Pim van der Harst, Duanping Liao, Joshua C. Bis, Kari E. North, Matteo Barcella, Michel G. Nivard, Jitender Kumar, Andrew Wong, Dewleen G. Baker, G. Ehret, Sulayma Albarwani, Kathleen F. Kerr, Quenna Wong, Ville Huikari, Alexander Kluttig, Andrew P. Morris, Eco J. C. de Geus, Albertine J. Oldehinkel, Ann-Christine Syvänen, Martina Mueller-Nurasyid, Yong Li, Marcel den Hoed, Henning Tiemeier, Henriette E. Meyer zu Schwabedissen, Dorret I. Boomsma, Joop D. Lefrandt, Mohammad Hadi Zafarmand, Victoria B. Risbrough, Halina Greiser, Bruce M. Psaty, Oscar H. Franco, Niek Verweij, Cees A. Swenne, Antti M. Kiviniemi, Konstantin Strauch, Markus Juonala, Zhu Ming Zhang, Nicholas L. Smith, Olli T. Raitakari, Daiane Hemerich, Daniel T. O'Connor, Christopher J. O'Donnell, Riad Bayoumi, Peter Friberg, Alvaro Alonso, Julian F. Thayer, Caroline M. Nievergelt, Delilah Zabaneh, Steven A. Lubitz, Tomas Axelsson, Terho Lehtimäki, Daniele Cusi, Eric A. Whitsel, Arie M. van Roon, Kjell Nikus, Bruno H. Stricker, Bouwe P. Krijthe, Stefan Kääb, Lars Lind, Abdel Abdellaoui, Timothy A. Thornton, Anubha Mahajan, Johan Sundström, Nona Sotoodehnia, Charles Kooperberg, Moritz F. Sinner, Leo-Pekka Lyytikäinen, Xavier Jouven, Tanja G. M. Vrijkotte, Sander W. van der Laan, Tatiana Kuznetsova, Patrick T. Ellinor, Alexander P. Reiner, Ilja M. Nolte, Marian C. Limacher, Paul I.W. de Bakker, Ahmad Vaez, Albert Hofman, Meena Kumari, Folkert W. Asselbergs, Juhani Junttila, Bram Dierckx, Marjo-Riitta Järvelin, Ingrid E. Christophersen, Annie Britton, Cathy C. Laurie, Phyllis K. Stein, Katarzyna Stolarz-Skrzypek, Juha Auvinen, Alexander Teumer, Vilmantas Giedraitis, Foram N. Ashar, Jenny van Dongen, David S. Siscovick, Markku Eskola, Jussi Hernesniemi, Janine F. Felix, M. Loretto Munoz, Jessica van Setten, Yun Li, Bianca J. J. M. Brundel, Christine M. Albert, Annette Peters, Jerome I. Rotter, Nina Hutri-Kähönen, Mark A. Geyer, Lesley E. Tinker, Vinicius Tragante, Susan R. Heckbert, Alan B. Zonderman, John D. Rioux, Kent D. Taylor, Shih-Jen Hwang, Johan Ormel, Mike A. Nalls, Erik Ingelsson, Kirk C. Wilhelmsen, John S. Floras, Diana Kuh, Elsayed Z. Soliman, Henry J. Lin, Brenda W.J.H. Penninx, Mika Kivimäki, Maaike G. J. Gademan, Jouke-Jan Hottenga, Mika Kähönen, Gerjan Navis, Siegfried Perz, Tamar Sofer, Catharina A. Hartman, Barbara McKnight, Jan A. Kors, Rick Jansen, Melanie Waldenberger, Nina Mononen, Heikki V. Huikuri, Azmeraw T. Amare, Mohammad L. Hassan, Jan A. Staessen, Adam X. Maihofer, Erika Salvi, Rob J. Bieringa, Benedikt von der Heyde, Andrea Dietrich, Peter J. van der Most, Philippe Goyette, Harriëtte Riese, Michele K. Evans, Stephanie M. Gogarten, Jean-Claude Tardif, Harold Snieder, Adrienne M. Stilp, Christy L. Avery, Johannes H. Smit, Gonneke Willemsen, Yuri Milaneschi, André G. Uitterlinden, Cecilia M. Lindgren, VU University medical center, APH - Mental Health, Psychiatry, Physiology, ACS - Heart failure & arrhythmias, APH - Methodology, and APH - Digital Health
Subjects: 0301 basic medicine, Genetics, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Disease risk, Heart rate variability, 030217 neurology & neurosurgery
Abstract: Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.
Published: 2017

19. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author: Gerjan Navis, Moritz F. Sinner, Kathleen F. Kerr, Heikki V. Huikuri, Daniele Cusi, Oscar H. Franco, Marian C. Limacher, Charles Kooperberg, Gabrielle Boucher, Riad Bayoumi, Juhani Junttila, Ann-Christine Syvänen, Andrew P. Morris, Anubha Mahajan, Andreas Voss, Paul I.W. de Bakker, Patrick T. Ellinor, Phyllis K. Stein, Janine F. Felix, Mark A. Geyer, Mike A. Nalls, Erik Ingelsson, Vinicius Tragante, Joshua C. Bis, Kari E. North, Jean-Claude Tardif, Harold Snieder, Azmeraw T. Amare, Katarzyna Stolarz-Skrzypek, Markku Eskola, Ilja M. Nolte, Tanja G. M. Vrijkotte, Elsayed Z. Soliman, Deepali Jaju, Melanie Neijts, Adrienne M. Stilp, Mika Kähönen, Henry J. Lin, Jessica van Setten, Meena Kumari, Halina Greiser, John S. Floras, Henriette E. Meyer zu Schwabedissen, Mohammad Hadi Zafarmand, Dewleen G. Baker, Rick Jansen, Cathy C. Laurie, Matteo Barcella, Christy L. Avery, Stefan Kääb, Michel G. Nivard, Jitender Kumar, Lars Lind, Alexander Teumer, Johan Sundström, Kirk C. Wilhelmsen, Barbara McKnight, Vilmantas Giedraitis, Johannes H. Smit, Gonneke Willemsen, Nona Sotoodehnia, Michele K. Evans, Christine M. Albert, Kent D. Taylor, Marcel den Hoed, James D. Stewart, Peter Friberg, Alvaro Alonso, Susan R. Heckbert, Kjell Nikus, Siegfried Perz, André G. Uitterlinden, Bruce M. Psaty, Antti M. Kiviniemi, G. Ehret, Jouke-Jan Hottenga, Sulayma Albarwani, Bouwe P. Krijthe, Timothy A. Thornton, Caroline M. Nievergelt, Delilah Zabaneh, Zhu Ming Zhang, Annie Britton, Ingrid E. Christophersen, Adam X. Maihofer, Juha Auvinen, David S. Siscovick, Arie M. van Roon, Xavier Jouven, Stephanie M. Gogarten, M. Loretto Munoz, Erika Salvi, Folkert W. Asselbergs, Bram Dierckx, Marjo-Riitta Järvelin, Cecilia M. Lindgren, Yun Li, Quenna Wong, Alan B. Zonderman, Yuri Milaneschi, John D. Rioux, Brenda W.J.H. Penninx, Philippe Goyette, Niek Verweij, Harriëtte Riese, Bruno H. Stricker, Markus Juonala, Rob J. Bieringa, Arpi Minassian, Jenny van Dongen, Abdel Abdellaoui, Foram N. Ashar, Jan A. Kors, Albertine J. Oldehinkel, Jussi Hernesniemi, Sander W. van der Laan, Ahmad Vaez, Nina Hutri-Kähönen, Annette Peters, Lesley E. Tinker, Albert Hofman, Dorret I. Boomsma, Victoria B. Risbrough, Tamar Sofer, Pim van der Harst, Konstantin Strauch, Steven A. Lubitz, Catharina A. Hartman, Jerome I. Rotter, Shih-Jen Hwang, Duanping Liao, Mika Kivimäki, Mohammad L. Hassan, Andrew Wong, Peter J. van der Most, Alexander Kluttig, Nina Mononen, Eco J. C. de Geus, Henning Tiemeier, Benedikt von der Heyde, Martina Müller-Nurasyid, Joop D. Lefrandt, Andrea Dietrich, Nicholas L. Smith, Terho Lehtimäki, Bianca J. J. M. Brundel, Jan A. Staessen, Cees A. Swenne, Julian F. Thayer, Daniel T. O'Connor, Christopher J. O'Donnell, Eric A. Whitsel, Tatiana Kuznetsova, Alexander P. Reiner, Johan Ormel, Ville Huikari, Yong Li, Tomas Axelsson, Olli T. Raitakari, Daiane Hemerich, Leo-Pekka Lyytikäinen, Maaike G. J. Gademan, Melanie Waldenberger, Diana Kuh, Ehret, Georg Benedikt, APH - Personalized Medicine, APH - Global Health, Other Research, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, ARD - Amsterdam Reproduction and Development, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Physiology, ACS - Heart failure & arrhythmias, APH - Digital Health, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Value, Affordability and Sustainability (VALUE), Biological Psychology, Praxis, Environmental Geography (former), Child and Adolescent Psychiatry / Psychology, Rheumatology, Epidemiology, Medical Informatics, and Internal Medicine
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, Potassium Channels, Chemistry(all), Muscle Proteins, General Physics and Astronomy, Genome-wide association study, Blood Pressure, PEDIGREES, Bioinformatics, Biochemistry, Genome-wide association studies, Medical and Health Sciences, Cohort Studies, Heart Rate, Risk Factors, RGS Proteins/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, RECORDINGS, Heart rate variability, Vagal tone, European Continental Ancestry Group/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, ddc:616, Muscle Proteins/genetics, Multidisciplinary, digestive, oral, and skin physiology, Single Nucleotide, Multidisciplinary Sciences, Science & Technology - Other Topics, Heart Diseases/genetics/physiopathology, Erratum, circulatory and respiratory physiology, Heart Diseases, Science, Quantitative Trait Loci, RESPIRATORY SINUS ARRHYTHMIA, Quantitative trait locus, Biology, Physics and Astronomy(all), Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Article, PARASYMPATHETIC REGULATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Heart rate, Journal Article, Humans, Genetic Predisposition to Disease, COHORT, Polymorphism, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, MODULATOR, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), MORTALITY, Cardiovascular genetics, General Chemistry, Membrane hyperpolarization, ta3121, 030104 developmental biology, Expression quantitative trait loci, ATRIAL-FIBRILLATION, Potassium Channels/genetics, RGS Proteins, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74, Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.
Published: 2017

20. Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Author: Helen R. Warren, Bradford B. Worrall, Jorgen Engmann, Tom R. Gaunt, David Prieto-Merino, Usha Menon, Dennis O. Mook-Kanamori, Aroon D. Hingorani, Meena Kumari, Mika Kivimäki, Ang Zhou, Michael V. Holmes, Aleksandra Gentry-Maharaj, Barbara J. Jefferis, Delilah Zabaneh, Mark J. Caulfield, Reecha Sofat, Renée de Mutsert, Chris Power, Yoav Ben-Shlomo, J. Wouter Jukema, Tom Palmer, Richard W Morris, Tina Shah, Juan P. Casas, Diana Kuh, Max Moldovan, Debbie A Lawlor, Jacqueline F. Price, Andrew Wong, Raymond Noordam, Caroline Dale, Steve E. Humphries, Naveed Sattar, Stella Trompet, Jon White, Stela McLachlan, George Davey Smith, Frank Dudbridge, Patricia B. Munroe, Andy Ryan, Elina Hyppönen, Ghazaleh Fatemifar, Dale, Caroline E, Fatemifar, Ghazaleh, Palmer, Tom M, White, Jon, Hyppönen, Elina, Zhou, Ang, and Casas, Juan P
Subjects: 0301 basic medicine, medicine.medical_specialty, Mendelian randomization analysis, body fat distribution, body mass index, Coronary Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Waist–hip ratio, Physiology (medical), Internal medicine, Diabetes mellitus, Mendelian randomization, medicine, Body Fat Distribution, Humans, Longitudinal Studies, Prospective Studies, Stroke, Adiposity, adiposity, business.industry, Type 2 Diabetes Mellitus, Odds ratio, Mendelian Randomization Analysis, medicine.disease, stroke, Observational Studies as Topic, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Cardiology, waist-hip ratio, Cardiology and Cardiovascular Medicine, business, Body mass index, coronary artery disease, Bristol Population Health Science Institute
Abstract: Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28–1.71), similar to findings for BMI (1 SD≈4.6 kg/m 2 ; OR for CHD, 1.36; 95% CI, 1.22–1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03–1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38–2.42) and OR, 1.98 (95% CI, 1.41–2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%–77% per 1 SD). Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.
Published: 2017

21. Abstract 23: Identification of NCF4 as a Novel Regulator in Arterial Remodeling and Advanced Atherosclerosis

Author: Alexandra Bäcklund, Karl Gertow, Hong Jin, Lina Olsson, Maria Gonzalez-Diez, Maria Sabater-Lleal, Rona J Strawbridge, Bengt Sennblad, John Öhrvik, Delilah Zabaneh, Sonia Shah, Fabrizio Veglia, Lasse Folkersen, Bruna Gigante, Karin Leander, Max Vikström, Angela Silveira, Gualtiero I Colombo, Anders Gabrielsen, Ulf Hedin, Anders Franco-Cereceda, Gabrielle Paulsson-Berne, Kristiina Nyyssönen, Tomi-pekka Tuomainen, Kai Savonen, Rainer Rauramaa, Andries J Smit, Philippe Giral, Elmo Mannarino, Sander W van der Laan, Gerard Pasterkamp, Göran K Hansson, Per Eriksson, Damiano Baldassarre, Elena Tremoli, Ulf de Faire, Steve E Humphries, Anders Hamsten, Rikard Holmdahl, and Lars Maegdefessel
Subjects: cardiovascular system, Cardiology and Cardiovascular Medicine
Abstract: Arterial wall remodeling is a central multifactorial process in the development and progression of cardiovascular diseases. We employed an approach aimed at observing genetic variants associated with the progression of carotid intima-media thickness (cIMT) in order to identify novel pathways effecting vessel remodeling. This was achieved by conducting gene-centric analysis of 400,000 variants in 3,042 subjects with repeated cIMT measurements. Rs16997464 on chr22 intergenic between neutrophil cytosolic factor-4 ( NCF4) and colony stimulating factor 2 receptor beta ( CSF2RB ) was associated with cIMT progression at array-wide significance (p -7 ). The potential causative genes within this locus were investigated using a human vascular and non-vascular tissue biobank. Expression of 9 genes near rs16997464, were analyzed with the most significant association being with NCF4 in aortic adventitia. The effect of the variant on the function of the NCF4 gene product was further analyzed by comparing the oxidative burst capacity of neutrophils from subjects with different rs16997464 genotypes. We observed that neutrophils homozygous for the minor T allele, associated with slower cIMT progression, produced more extracellular ROS than neutrophils homozygous for the G allele, indicating a functional effect of rs16997464 on the NCF4 gene product p40 phox , a component of the NADPH oxidase 2 complex (NOX2). In parallel, we investigated if the chr22 locus also influenced the cellular composition of the atherosclerotic plaque, by utilizing data from the Athero-Express Biobank. Here we found that the minor T allele associated with a higher smooth muscle cell (SMC) content in the plaque. Finally, using a partial ligation model in mice where ncf4 is mutated, resulting in a reduced but not absent NOX2-associated ROS formation, we observed a reduced neointima formation in the ncf4 -mutated strain compared with wild-type littermates. Thus, this study identified rs16997464 in the NCF4-CSF2RB locus as a novel genetic determinant of cIMT progression, and provides evidence suggesting that NCF4 is involved in SMC proliferation and alteration of vessel wall pathophysiology.
Published: 2017

22. Fine mapping genetic associations between the HLA region and extremely high intelligence

Author: David Lubinski, Delilah Zabaneh, William G. Iacono, Gerome Breen, Michael A. Simpson, Michael B. Miller, Robert Plomin, Martha Putallaz, Matt McGue, and Eva Krapohl
Subjects: 0301 basic medicine, Genetics, Male, Multifactorial Inheritance, Multidisciplinary, Genotype, Intelligence, Chromosome Mapping, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 030104 developmental biology, Missing heritability problem, HLA Antigens, Case-Control Studies, Genetic variation, SNP, Humans, Female
Abstract: General cognitive ability (intelligence) is one of the most heritable behavioural traits and most predictive of socially important outcomes and health. We hypothesized that some of the missing heritability of IQ might lie hidden in the human leukocyte antigen (HLA) region, which plays a critical role in many diseases and traits but is not well tagged in conventional GWAS. Using a uniquely powered design, we investigated whether fine-mapping of the HLA region could narrow the missing heritability gap. Our case-control design included 1,393 cases with extremely high intelligence scores (top 0.0003 of the population equivalent to IQ > 147) and 3,253 unselected population controls. We imputed variants in 200 genes across the HLA region, one SNP (rs444921) reached our criterion for study-wide significance. SNP-based heritability of the HLA variants was small and not significant (h2 = 0.3%, SE = 0.2%). A polygenic score from the case-control genetic association analysis of SNPs in the HLA region did not significantly predict individual differences in intelligence in an independent unselected sample. We conclude that although genetic variation in the HLA region is important to the aetiology of many disorders, it does not appear to be hiding much of the missing heritability of intelligence.
Published: 2017

23. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author: Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. Chines, Dharambir KSanghera, Peter Donnelly, [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Natl Inst Hlth, Ctr Genome Sci, Gangoe Myeon, Yeonje Ri, South Korea [ 3 ] Univ London Imperial Coll Sci Technol & Med, London, England [ 4 ] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA [ 5 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England [ 6 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 7 ] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA [ 8 ] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA [ 9 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England [ 10 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England [ 11 ] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan [ 12 ] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore [ 13 ] Wellcome Trust Sanger Inst, Cambridge, England [ 14 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 15 ] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA [ 16 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 17 ] Univ Eastern Finland, Inst Biomed, Kuopio, Finland [ 18 ] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore [ 19 ] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore [ 20 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 21 ] Univ Milan, Dept Pharmacol Sci, Milan, Italy [ 22 ] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France [ 23 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 24 ] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Shanghai 200030, Peoples R China [ 25 ] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England [ 26 ] Heart England Natl Hlth Serv NHS Fdn Trust, Ctr Biomed Res, Birmingham, W Midlands, England [ 27 ] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England [ 28 ] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 29 ] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan [ 30 ] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA [ 31 ] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia [ 32 ] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia [ 33 ] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia [ 34 ] Univ Chicago, Dept Med, Chicago, IL 60637 USA [ 35 ] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA [ 36 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 37 ] Landspitali Univ Hosp, Reykjavik, Iceland [ 38 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 39 ] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany [ 40 ] Nanyang Technol Univ, Lee Kong Chian LKC Sch Med, Singapore 639798, Singapore [ 41 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 42 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 43 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 44 ] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA [ 45 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37212 USA [ 46 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 47 ] Univ Edinburgh, Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland [ 48 ] CNRS, Unite Mixte Rech UMR 8199, Inst Biol, Lille, France [ 49 ] Univ Lille 2, Inst Pasteur, Lille, France [ 50 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England [ 51 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England [ 52 ] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China [ 53 ] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan [ 54 ] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan [ 55 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 56 ] China Med Univ, Sch Chinese Med, Taichung, Taiwan [ 57 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 58 ] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore [ 59 ] Indian Council Med Res, Adv Ctr Genom Diabet, Madras Diabet Res Fdn, Dept Mol Genet, Madras, Tamil Nadu, India [ 60 ] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 441749, South Korea [ 61 ] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea [ 62 ] Natl Taiwan Univ, Sch Med, Grad Inst Clin Med, Taipei 10764, Taiwan [ 63 ] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA [ 64 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 65 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 66 ] Ealing Hosp NHS Trust, Southall, Middx, England [ 67 ] Karolinska Inst, Inst Environm Med, Divis Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 68 ] Harokopio Univ, Dept Dietet Nutr, Athens, Greece [ 69 ] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland [ 70 ] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece [ 71 ] INSERM, UMR 1087, Nantes, France [ 72 ] CNRS, UMR 6291, Nantes, France [ 73 ] Univ Nantes, Nantes, France [ 74 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland [ 75 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 76 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 77 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 78 ] Netherlands Consortium Healthy Ageing, Netherland Genom Initiat, Rotterdam, Netherlands [ 79 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 80 ] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England [ 81 ] Iceland Heart Assoc, Kopavogur, Iceland [ 82 ] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 83 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 84 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 85 ] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland [ 86 ] Folkhalsan Res Ctr, Helsinki, Finland [ 87 ] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico [ 88 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 89 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 90 ] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA [ 91 ] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA [ 92 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 93 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 94 ] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA [ 95 ] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England [ 96 ] Vaasa Hlth Care Ctr, Vaasa, Finland [ 97 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 98 ] Harvard Univ, Sch Med, Boston, MA USA [ 99 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 100 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 101 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 102 ] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden [ 103 ] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany [ 104 ] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 105 ] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany [ 106 ] Helmholtz Zentrum Muenchen, Munich, Germany [ 107 ] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany [ 108 ] German Ctr Diabet Res DZD, Neuherberg, Germany [ 109 ] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England [ 110 ] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan [ 111 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 112 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 113 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway [ 114 ] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands [ 115 ] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA [ 116 ] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia [ 117 ] UCL, Inst Cardiovasc Sci, London, England [ 118 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA [ 119 ] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan [ 120 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 121 ] Univ Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 122 ] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan [ 123 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 124 ] Aga Khan Univ, Dept Med, Karachi, Pakistan [ 125 ] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia [ 126 ] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia [ 127 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 128 ] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia [ 129 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 130 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 131 ] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan [ 132 ] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka [ 133 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 134 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413
Published: 2014

24. Gene-Centric Analysis Identifies Variants Associated With Interleukin-6 Levels and Shared Pathways With Other Inflammation Markers

Author: Meena Kumari, John C. Whittaker, Michael V. Holmes, Reecha Sofat, Juan P. Casas, Tom R. Gaunt, Sonia Shah, Aroon D. Hingorani, Ian N. M. Day, Daniel I. Swerdlow, Mika Kivimäki, Tina Shah, Delilah Zabaneh, Philippa J. Talmud, and Steve E. Humphries
Subjects: Male, Nonsynonymous substitution, Genotype, Genome-wide association study, Coronary Artery Disease, Disease, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Autoimmune Diseases, Risk Factors, ABO blood group system, Genetics, Humans, Medicine, Risk factor, Allele, Interleukin 6, Alleles, Genetics (clinical), Aged, Inflammation, biology, Interleukin-6, business.industry, C-reactive protein, Middle Aged, Receptors, Interleukin-6, C-Reactive Protein, Phenotype, Genetic Loci, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Genome-Wide Association Study
Abstract: Background— Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. Methods and Results— We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women’s Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci ( IL6R/TDRD10 , HLA-DRB1 , BUD13 , SEZ6L , IL1RN , TRIB3 , and ABO ) were associated with IL-6 ( P –5 ), although none were associated with the IL6 gene itself. With the exception of TRIB3 , all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r 2 >0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration ( P –5 ). An IL-6–specific weighted allele score explained 2% of the variance of log IL-6 levels ( P =2.4410 –22 ) in Whitehall II and 1% ( P =1.910 –8 ) in British Women’s Heart and Health Studies. Conclusions— Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases.
Published: 2013

25. Association of the TSHR gene with Graves' disease: the first disease specific locus

Author: Stephen C. L. Gough, Angie P Green, Jayne A. Franklyn, Delilah Zabaneh, Bryan M. Dechairo, Thomas Heiberg Brix, Anthony P. Weetman, J. E. Collins, Gary Dawson, Laszlo Hegedüs, Oliver J. Brand, Ian Mackay, Wilmar M. Wiersinga, John Wass, Bruce G. Robinson, John M. C. Connell, Penny J. Hunt, Alisoun H. Carey, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Endocrinology
Subjects: Linkage disequilibrium, endocrine system, endocrine system diseases, Graves' disease, Population, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Genetics, medicine, SNP, Humans, education, Genotyping, Genetics (clinical), education.field_of_study, Haplotype, Chromosome Mapping, Receptors, Thyrotropin, medicine.disease, Graves Disease, United Kingdom, Genetics, Population, Haplotypes, Case-Control Studies
Abstract: The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD 'blocks' and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P
Published: 2016

26. Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians

Author: Aimo Ruokonen, Jaspal S. Kooner, Delilah Zabaneh, Joban Sehmi, Paul Elliott, James Scott, Piyush Jain, Philippe Froguel, John C. Chambers, Weihua Zhang, Marjo-Riitta Järvelin, David J. Balding, Mark I. McCarthy, and Medical Research Council (MRC)
Subjects: Blood Glucose, Male, Linkage disequilibrium, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Blood Pressure, Type 2 diabetes, CIRCADIAN CLOCK, VARIANTS, 0302 clinical medicine, Risk Factors, POPULATION, 11 Medical and Health Sciences, 2. Zero hunger, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Middle Aged, PREVALENCE, Europe, OBESITY, Hypertension, Original Article, Female, Life Sciences & Biomedicine, Asian Continental Ancestry Group, Adult, medicine.medical_specialty, Population, European Continental Ancestry Group, Blood sugar, India, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Environment, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Asian People, Internal medicine, Internal Medicine, medicine, Genetics, Humans, TOLERANCE, Risk factor, GENOME-WIDE ASSOCIATION, education, Life Style, 030304 developmental biology, Aged, Science & Technology, Receptor, Melatonin, MT2, Genetic Variation, medicine.disease, POLYMORPHISM, Diet, Endocrinology, Diabetes Mellitus, Type 2, FASTING GLUCOSE, Genome-Wide Association Study
Abstract: OBJECTIVE Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians. RESEARCH DESIGN AND METHODS We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians. RESULTS We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians. CONCLUSIONS Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.
Published: 2016

27. Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Aysu, Okbay, Bart M L, Baselmans, Jan-Emmanuel De, Neve, Patrick, Turley, Michel G, Nivard, Mark Alan, Fontana, S Fleur W, Meddens, Richard Karlsson, Linnér, Cornelius A, Rietveld, Jaime, Derringer, Jacob, Gratten, James J, Lee, Jimmy Z, Liu, Ronald, de Vlaming, Tarunveer S, Ahluwalia, Jadwiga, Buchwald, Alana, Cavadino, Alexis C, Frazier-Wood, Nicholas A, Furlotte, Victoria, Garfield, Marie Henrike, Geisel, Juan R, Gonzalez, Saskia, Haitjema, Robert, Karlsson, Sander W, van der Laan, Karl-Heinz, Ladwig, Jari, Lahti, Sven J, van der Lee, Penelope A, Lind, Tian, Liu, Lindsay, Matteson, Evelin, Mihailov, Michael B, Miller, Camelia C, Minica, Ilja M, Nolte, Dennis, Mook-Kanamori, Peter J, van der Most, Christopher, Oldmeadow, Yong, Qian, Olli, Raitakari, Rajesh, Rawal, Anu, Realo, Rico, Rueedi, Börge, Schmidt, Albert V, Smith, Evie, Stergiakouli, Toshiko, Tanaka, Kent, Taylor, Gudmar, Thorleifsson, Juho, Wedenoja, Juergen, Wellmann, Harm-Jan, Westra, Sara M, Willems, Wei, Zhao, Najaf, Amin, Andrew, Bakshi, Sven, Bergmann, Gyda, Bjornsdottir, Patricia A, Boyle, Samantha, Cherney, Simon R, Cox, Gail, Davies, Oliver S P, Davis, Jun, Ding, Nese, Direk, Peter, Eibich, Rebecca T, Emeny, Ghazaleh, Fatemifar, Jessica D, Faul, Luigi, Ferrucci, Andreas J, Forstner, Christian, Gieger, Richa, Gupta, Tamara B, Harris, Juliette M, Harris, Elizabeth G, Holliday, Jouke-Jan, Hottenga, Philip L De, Jager, Marika A, Kaakinen, Eero, Kajantie, Ville, Karhunen, Ivana, Kolcic, Meena, Kumari, Lenore J, Launer, Lude, Franke, Ruifang, Li-Gao, David C, Liewald, Marisa, Koini, Anu, Loukola, Pedro, Marques-Vidal, Grant W, Montgomery, Miriam A, Mosing, Lavinia, Paternoster, Alison, Pattie, Katja E, Petrovic, Laura, Pulkki-Råback, Lydia, Quaye, Katri, Räikkönen, Igor, Rudan, Rodney J, Scott, Jennifer A, Smith, Angelina R, Sutin, Maciej, Trzaskowski, Anna E, Vinkhuyzen, Lei, Yu, Delilah, Zabaneh, John R, Attia, David A, Bennett, Klaus, Berger, Lars, Bertram, Dorret I, Boomsma, Harold, Snieder, Shun-Chiao, Chang, Francesco, Cucca, Ian J, Deary, Cornelia M, van Duijn, Johan G, Eriksson, Ute, Bültmann, Eco J C, de Geus, Patrick J F, Groenen, Vilmundur, Gudnason, Torben, Hansen, Catharine A, Hartman, Claire M A, Haworth, Caroline, Hayward, Andrew C, Heath, David A, Hinds, Elina, Hyppönen, William G, Iacono, Marjo-Riitta, Järvelin, Karl-Heinz, Jöckel, Jaakko, Kaprio, Sharon L R, Kardia, Liisa, Keltikangas-Järvinen, Peter, Kraft, Laura D, Kubzansky, Terho, Lehtimäki, Patrik K E, Magnusson, Nicholas G, Martin, Matt, McGue, Andres, Metspalu, Melinda, Mills, Renée, de Mutsert, Albertine J, Oldehinkel, Gerard, Pasterkamp, Nancy L, Pedersen, Robert, Plomin, Ozren, Polasek, Christine, Power, Stephen S, Rich, Frits R, Rosendaal, Hester M, den Ruijter, David, Schlessinger, Helena, Schmidt, Rauli, Svento, Reinhold, Schmidt, Behrooz Z, Alizadeh, Thorkild I A, Sørensen, Tim D, Spector, John M, Starr, Kari, Stefansson, Andrew, Steptoe, Antonio, Terracciano, Unnur, Thorsteinsdottir, A Roy, Thurik, Nicholas J, Timpson, Henning, Tiemeier, André G, Uitterlinden, Peter, Vollenweider, Gert G, Wagner, David R, Weir, Jian, Yang, Dalton C, Conley, George Davey, Smith, Albert, Hofman, Magnus, Johannesson, David I, Laibson, Sarah E, Medland, Michelle N, Meyer, Joseph K, Pickrell, Tõnu, Esko, Robert F, Krueger, Jonathan P, Beauchamp, Philipp D, Koellinger, Daniel J, Benjamin, Meike, Bartels, and David, Cesarini
Subjects: Journal Article, Medizin, Genetics, Article
Abstract: We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
Published: 2016

28. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Sharon L.R. Kardia, Melinda Mills, Ian J. Deary, Sven Bergmann, Magnus Johannesson, Igor Rudan, Nicholas J. Timpson, Richa Gupta, Hester M. den Ruijter, Rico Rueedi, Lars Bertram, Juliette Harris, Jennifer A. Smith, Eero Kajantie, Jian Yang, David C. Liewald, Ronald de Vlaming, Anu Realo, Jessica D. Faul, Patrik K. E. Magnusson, Jadwiga Buchwald, Philip L. De Jager, Rajesh Rawal, Marisa Koini, K. Petrovic, Unnur Thorsteinsdottir, Pedro Marques-Vidal, Roy Thurik, Evie Stergiakouli, Ivana Kolcic, William G. Iacono, Laura D. Kubzansky, Jaakko Kaprio, Behrooz Z. Alizadeh, Samantha Cherney, Reinhold Schmidt, Vilmundur Gudnason, Nicholas A. Furlotte, Nicholas G. Martin, Delilah Zabaneh, Rebecca T. Emeny, Eco J. C. de Geus, Klaus Berger, Lude Franke, Sven J. van der Lee, S. Fleur W. Meddens, Bart M. L. Baselmans, Dalton Conley, Jouke-Jan Hottenga, David A. Bennett, Saskia Haitjema, Jun Ding, Elina Hyppönen, Kari Stefansson, Henning Tiemeier, Grant W. Montgomery, Michelle N. Meyer, James J. Lee, Aysu Okbay, Lei Yu, Gyda Bjornsdottir, Marie Henrike Geisel, Albertine J. Oldehinkel, Liisa Keltikangas-Järvinen, George Davey Smith, Harold Snieder, Juho Wedenoja, Frits R. Rosendaal, Michel G. Nivard, Simon R. Cox, Christine Power, Dorret I. Boomsma, Börge Schmidt, David A. Hinds, Philipp Koellinger, Harm-Jan Westra, Terho Lehtimäki, Alison Pattie, Jan-Emmanuel De Neve, Torben Hansen, John M. Starr, Albert V. Smith, Antonio Terracciano, Juergen Wellmann, Albert Hofman, Katri Räikkönen, Patrick Turley, Andrew Steptoe, Jimmy Z. Liu, Evelin Mihailov, Jari Lahti, Marika Kaakinen, David R. Weir, Cornelia M. van Duijn, Maciej Trzaskowski, David Cesarini, Najaf Amin, Lydia Quaye, Sara M. Willems, Ghazaleh Fatemifar, Christopher Oldmeadow, Ville Karhunen, Alana Cavadino, Juan R. González, Caroline Hayward, Penelope A. Lind, Tamara B. Harris, Jaime Derringer, Camelia C. Minică, Jacob Gratten, Patrick J. F. Groenen, Ozren Polasek, Anu Loukola, Peter Vollenweider, Christian Gieger, Rodney J. Scott, Lindsay K. Matteson, Meike Bartels, Andrew Bakshi, David Laibson, Andrew C. Heath, Daniel J. Benjamin, Stephen S. Rich, Claire M. A. Haworth, C.A. Hartman, Angelina R. Sutin, Tian Liu, Johan G. Eriksson, Robert Plomin, Francesco Cucca, John Attia, Tarunveer S. Ahluwalia, Andreas J. Forstner, Gudmar Thorleifsson, Rauli Svento, Ute Bültmann, Olli T. Raitakari, Karl-Heinz Jöckel, Mark Alan Fontana, Oliver S. P. Davis, Yong Qian, Anna A. E. Vinkhuyzen, Wei Zhao, Elizabeth G. Holliday, Andres Metspalu, Alexis C. Frazier-Wood, Meena Kumari, Nese Direk, Miriam A. Mosing, Ilja M. Nolte, Sander W. van der Laan, Matt McGue, Tim D. Spector, Marjo-Riitta Järvelin, Peter Eibich, Nancy L. Pedersen, David Schlessinger, Toshiko Tanaka, Dennis O. Mook-Kanamori, Luigi Ferrucci, Gerard Pasterkamp, Jonathan P. Beauchamp, Robert Karlsson, Lenore J. Launer, Helena Schmidt, Renée de Mutsert, Gert G. Wagner, Peter Kraft, Joseph K. Pickrell, Thorkild I. A. Sørensen, André G. Uitterlinden, Patricia A. Boyle, Cornelius A. Rietveld, Robert F. Krueger, Karl-Heinz Ladwig, Michael B. Miller, Sarah E. Medland, Tõnu Esko, Kent D. Taylor, Lavinia Paternoster, Peter J. van der Most, Richard Karlsson Linnér, Laura Pulkki-Råback, Gail Davies, Victoria Garfield, Shun-Chiao Chang, Ruifang Li-Gao, Applied Economics, Pathology, Epidemiology, Public Health, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Ophthalmology, Social Science Genetic Association Consortium (SSGAC), CHARGE Consortium, Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Hyppönen, Elina, Cesarini, David, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], University of Queensland [Brisbane], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Tampere University Hospital, University of Turku, King‘s College London, University of Helsinki, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Birmingham City University (BCU), Helmholtz-Zentrum München (HZM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Edinburgh, Florida State University [Tallahassee] (FSU), Wuhan University [China], Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Erasmus University Rotterdam, National Institute for Health and Welfare [Helsinki], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and LifeLines Cohort Study
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, well-being, neuroticism, Anxiety Disorders/genetics, Bayes Theorem, Depression/genetics, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Genetics & Heredity, RISK, Genetics, PERSONALITY, [QFIN]Quantitative Finance [q-fin], Depression, HERITABILITY, COMMON VARIANTS, 11 Medical And Health Sciences, Anxiety Disorders, Neuroticism, depression, Behavioural genetics, Life Sciences & Biomedicine, Biology, personality, genetic, epidemiology, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Journal Article, Human height, Subjective well-being, behavioural genetics, METAANALYSIS, Genetic association, HAPPINESS, Science & Technology, MAJOR DEPRESSION, 06 Biological Sciences, Heritability, 030104 developmental biology, genome-wide association studies, HUMAN HEIGHT, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis
Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
Published: 2016

29. A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium

Author: Aroon D. Hingorani, Mika Kivimäki, Aaron R. Folsom, Ethan M. Lange, Delilah Zabaneh, David Green, Meena Kumari, Leslie A. Lange, Weihong Tang, Nicholas L. Smith, Brendan J. Keating, Kari E. North, Joseph A.C. Delaney, Kira C. Taylor, Steve E. Humphries, Russell P. Tracy, Christopher J. O'Donnell, and Alexander P. Reiner
Subjects: Adult, Male, Candidate gene, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, chemistry.chemical_compound, hemic and lymphatic diseases, Genetics, Humans, SNP, Genetic Predisposition to Disease, cardiovascular diseases, Molecular Biology, Gene, Genetics (clinical), Aged, Factor VII, Association Studies Articles, General Medicine, Middle Aged, Black or African American, chemistry, Cardiovascular Diseases, Female, Candidate Disease Gene
Abstract: Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
Published: 2011

30. Genetic Variants Associated with von Willebrand Factor Levels in Healthy Men and Women Identified Using the HumanCVD BeadChip

Author: Michael Marmot, Gordon D.O. Lowe, Elina Hyppönen, Reecha Sofat, Delilah Zabaneh, Jutta Palmen, Santiago Rodriguez, Juan P. Casas, John C. Whittaker, Richard W Morris, Meena Kumari, Mika Kivimäki, Tom R. Gaunt, Diane J. Berry, George Davey Smith, Peter H. Whincup, Sonia Shah, Ann Rumley, Ian N. M. Day, Chris Power, Philippa J. Talmud, Steve E. Humphries, Fotios Drenos, Aroon D. Hingorani, Tina Shah, Debbie A Lawlor, Jacky Pallas, and Shah Ebrahim
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, biology, Genetic variants, Locus (genetics), Single-nucleotide polymorphism, Von Willebrand factor, hemic and lymphatic diseases, ABO blood group system, Genotype, biology.protein, SNP, Allele, Genetics (clinical), circulatory and respiratory physiology
Abstract: We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.
Published: 2011

31. Heritability and genetic correlations of insulin resistance and component phenotypes in Asian Indian families using a multivariate analysis

Author: James Scott, John C. Chambers, Paul Elliott, Delilah Zabaneh, Jaspal S. Kooner, and David J. Balding
Subjects: Adult, Blood Glucose, Male, Multivariate analysis, Systole, Endocrinology, Diabetes and Metabolism, India, Coronary Disease, Biology, Body Mass Index, Insulin resistance, Diastole, Diabetes mellitus, Internal Medicine, medicine, Humans, Family, Age of Onset, Triglycerides, Hypolipidemic Agents, Glycated Hemoglobin, Genetics, Waist-Hip Ratio, Asian Indian, Patient Selection, Cholesterol, HDL, Middle Aged, Heritability, medicine.disease, Obesity, Phenotype, United Kingdom, Diabetes Mellitus, Type 2, Multivariate Analysis, Female, Insulin Resistance, European Whites
Abstract: Insulin resistance and related metabolic disturbances are more common among Asian Indians than European whites. Little is known about the heritability of insulin resistance traits in Asian Indians. Our objective was to estimate heritabilities and genetic correlations in Asian Indian families.Phenotypic data were assembled for 181 UK Asian Indian probands with premature CHD, and their 1,454 first-, second- and third-degree relatives. We calculated (narrow-sense) heritabilities and genetic correlations for insulin resistance traits, and common environmental effects using all study participants and a multivariate model. The analysis was repeated in a subsample consisting of individuals not on drug therapy.Heritability estimates (SE) for individuals not on drug therapy were: BMI 0.31 (0.04), WHR 0.27 (0.04), systolic BP 0.29 (0.03), triacylglycerol 0.40 (0.04), HDL-cholesterol 0.53 (0.04), glucose 0.37 (0.03), HOMA of insulin resistance (HOMA-IR) 0.22 (0.04), and HbA(1c) 0.60 (0.04). We observed many significant genetic correlations between the traits, in particular between HOMA-IR and BMI. Heritability estimates were lower for all phenotypes when analysed among all participants.Genetic factors contribute to a significant proportion of the total variance in insulin resistance and related metabolic disturbances in Asian Indian CHD families.
Published: 2009

32. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance

Author: David B. Bentley, Andrew Owen, Alison J. Coffey, Delilah Zabaneh, Guy D. Leschziner, David J. Balding, Munir Pirmohamed, Jane Rogers, and Marvin Johnson
Subjects: Linkage disequilibrium, Single-nucleotide polymorphism, Biology, Linkage Disequilibrium, White People, Genetic variation, Genetics, Humans, Coding region, General Pharmacology, Toxicology and Pharmaceutics, Molecular Biology, Gene, Alleles, Genetics (clinical), Exome sequencing, Genetic association, Polymorphism, Genetic, Models, Genetic, Haplotype, Genetic Variation, Exons, Sequence Analysis, DNA, Drug Resistance, Multiple, Multidrug Resistance-Associated Protein 2, Haplotypes, Molecular Medicine, ATP-Binding Cassette Transporters, Multidrug Resistance-Associated Proteins
Abstract: Background The ATP-binding cassette (ABC) proteins are a superfamily of efflux pumps implicated as a mechanism for multidrug resistance in cytotoxic chemotherapy, immunosuppressive therapy, HIV and epilepsy. Genetic variation in P-glycoprotein, the product of the ABCB1 gene, is proposed to mediate de novo drug resistance, but associations between polymorphisms in ABCB1 and pharmacoresistance have produced conflicting results. Potential explanations for the inconsistency of results include inadequate characterization of gene structure, variation and linkage disequilibrium (LD) in ABCB1, as well as overlap in substrate specificity between ABCB1 and the various other drug transporters.Methods and results We undertook a fundamental analysis of gene structure, variation and LD in ABCB1 and four other drug transporter genes implicated in pharmacoresistance: ABCC1, ABCC2, ABCC5 and ABCB4. Manual annotation of the five genes revealed nine shorter alternative transcripts with new untranslated regions and one novel region of coding sequence, demonstrating that on-line annotations are incomplete. Sequencing of exons in 47 Caucasian individuals identified 75 novel single nucleotide polymorphisms (SNPs) previously undescribed in any public database, including 14 new coding sequence SNPs. Genotyping of 502 SNPs in 842 Caucasian individuals across the five genes revealed large blocks of high LD, and low haplotype diversity across all five genes that could be characterized by between 67 and 114 tagging SNPs, depending on the tagging criteria.Conclusion The study illustrates that publicly available data resources on genomic organization of genes and common variation can have important gaps and limitations, and establishes a comprehensive set of tagging SNPs for future association studies in pharmacoresistance. (C) 2006 Lippincott Williams & Wilkins.
Published: 2006

33. A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease

Author: Stephen C. L. Gough, Laszlo Hegedüs, Anthony P. Weetman, John A.H. Wass, Krishna Chatterjee, Jayne A. Franklyn, John M. C. Connell, Jenny C. Taylor, Delilah Zabaneh, Bruce G. Robinson, Thomas Heiberg Brix, Ian Mackay, Wilmar M. Wiersinga, Penny J. Hunt, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Endocrinology
Subjects: medicine.medical_specialty, endocrine system diseases, Genetic Linkage, Endocrinology, Diabetes and Metabolism, Graves' disease, Clinical Biochemistry, Context (language use), Disease, Human leukocyte antigen, Biochemistry, Statistics, Nonparametric, Cohort Studies, Endocrinology, Hypothyroidism, Genetic linkage, Internal medicine, medicine, Genetic predisposition, Chromosomes, Human, Humans, Family, Genetic Predisposition to Disease, Autoimmune disease, Genome, Human, business.industry, Biochemistry (medical), Thyroid, Chromosome Mapping, medicine.disease, Graves Disease, medicine.anatomical_structure, Immunology, Lod Score, business
Abstract: CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions. OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions. DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD. RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found. CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD.
Published: 2006

34. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels

Author: Marjo-Riitta Järvelin, Jaspal S. Kooner, Gonçalo R. Abecasis, Mark N. Wass, Michael J.E. Sternberg, Delilah Zabaneh, Yun Li, Paul Elliott, Clive J. Hoggart, Patrick H. Maxwell, Nelson B. Freimer, Henry K. Bayele, James Scott, Joban Sehmi, Leena Peltonen, Weihua Zhang, Surjit K. S. Srai, John C. Chambers, Mark I. McCarthy, and Aimo Ruokonen
Subjects: Genetics, Nonsynonymous substitution, 0303 health sciences, TMPRSS6, Genome-wide association study, Iron deficiency, Biology, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, Hepcidin, 030220 oncology & carcinogenesis, medicine, biology.protein, SNP, Hemoglobin, Allele, 030304 developmental biology
Abstract: We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09-0.17) g/dl lower per copy of allele A (P = 1.6 x 10(-13)). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.
Published: 2009

35. Common genetic variation near MC4R is associated with waist circumference and insulin resistance

Author: Jaspal S. Kooner, Delilah Zabaneh, John C. Chambers, Paul Elliott, James Scott, Yun Li, Weihua Zhang, David J. Balding, and Philippe Froguel
Subjects: Adult, Male, medicine.medical_specialty, Waist, Genetic Linkage, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, White People, Body Mass Index, Cohort Studies, Insulin resistance, Waist–hip ratio, Asian People, Risk Factors, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Alleles, Adiposity, Aged, Genome, Human, Waist-Hip Ratio, Homozygote, Genetic Variation, Middle Aged, medicine.disease, Circumference, Obesity, Endocrinology, Case-Control Studies, Receptor, Melanocortin, Type 4, Female, Insulin Resistance, Body mass index
Abstract: We carried out a genome-wide association study (318,237 SNPs) for insulin resistance and related phenotypes in 2,684 Indian Asians, with further testing in 11,955 individuals of Indian Asian or European ancestry. We found associations of rs12970134 near MC4R with waist circumference (P = 1.7 x 10(-9)) and, independently, with insulin resistance. Homozygotes for the risk allele of rs12970134 have approximately 2 cm increased waist circumference. Common genetic variation near MC4R is associated with risk of adiposity and insulin resistance.
Published: 2008

36. Gene-centric association signals for haemostasis and thrombosis traits identified with the HumanCVD BeadChip

Author: Juan P. Casas, Fotios Drenos, Meena Kumari, Aroon D. Hingorani, Delilah Zabaneh, Christophe Ladroue, John C. Whittaker, Mika Kivimäki, Anna L. Guyatt, Philippa J. Talmud, Steve E. Humphries, Ian N. M. Day, Tina Shah, Debbie A Lawlor, Gordon D.O. Lowe, Ann Rumley, Tom R. Gaunt, and Sonia Shah
Subjects: 0301 basic medicine, Blood Platelets, G-Protein-Coupled Receptor Kinase 5, Blood viscosity, DNA Mutational Analysis, Genome-wide association study, Single-nucleotide polymorphism, Cell Count, Biology, Fibrinogen, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Quantitative Trait, Heritable, Pleiotropy, medicine, Humans, Apolipoproteins A, Genetic Association Studies, Genetic association, Adaptor Proteins, Signal Transducing, Genetics, Clotting factor, Hemostasis, Factor VII, Macrophage Colony-Stimulating Factor, Membrane Transport Proteins, Thrombosis, Hematology, Blood Viscosity, Microarray Analysis, Microspheres, 030104 developmental biology, Phenotype, chemistry, Apolipoprotein A-V, Carrier Proteins, 030217 neurology & neurosurgery, medicine.drug
Abstract: SummaryCoagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women’s Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p = 1.30×10−6), GCKR (rs1260326, p = 1.63×10−6), ZNF259-APOA5 (rs651821, p = 7.17x10–6) with plasma viscosity; and at CSF1 (rs333948, p = 8.88×10−6) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p = 2.16×10−7) and plasma viscosity (p = 1.63×10−6), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p
Published: 2013

37. Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk

Author: Gualtiero I. Colombo, Jacqueline C. M. Witteman, Christopher J. O'Donnell, Damiano Baldassarre, Göran K. Hansson, Martin Farrall, Sonia Shah, Steve E. Humphries, Kai Savonen, Anders Hamsten, Lasse Folkersen, Per Eriksson, Philippe Giral, Pierre Fontanillas, Albert Hofman, Aroon D. Hingorani, Bruna Gigante, Maria Grazia Franzosi, Udo Seedorf, Anders Gabrielsen, Meena Kumari, Philippa J. Talmud, Fabrizio Veglia, Jennifer L. Bolton, Ann-Christine Syvänen, Jacqueline F. Price, Nilesh J. Samani, Elmo Mannarino, Ulf de Faire, Mika Kivimäki, Kristiina Nyyssönen, Andries J. Smit, Elena Tremoli, Robert Clarke, Christine Robertson, Delilah Zabaneh, André G. Uitterlinden, Angela Silveira, Tomi-Pekka Tuomainen, Bo Hedblad, Nicholas J. Wareham, Hugh Watkins, Malin Larsson, Muredach P. Reilly, Claudia Langenberg, Max Vikström, Bengt Sennblad, Olle Melander, John E. Deanfield, Karl Gertow, Benjamin F. Voight, John Öhrvik, Maryam Kavousi, Maria Sabater-Lleal, Karin Leander, Jeanette Erdmann, Rona J. Strawbridge, Anders Franco-Cereceda, Rainer Rauramaa, Stela McLachlan, Ulf Hedin, Cristiano Fava, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Epidemiology, and Internal Medicine
Subjects: Male, Pathology, Genome-wide association study, 030204 cardiovascular system & hematology, SUSCEPTIBILITY, ultrasounds, Coronary artery disease, Cohort Studies, 0302 clinical medicine, Risk Factors, Medicine, genetics, Myocardial infarction, Carotid intima-media thickness, Genetics (clinical), 0303 health sciences, education.field_of_study, CARDIOVASCULAR RISK, Nuclear Proteins, Middle Aged, Phenotype, Cardiology, cardiovascular system, Female, BCAR1-CFDP1-TMEM170A locus, Cardiology and Cardiovascular Medicine, coronary artery disease, medicine.medical_specialty, Population, Locus (genetics), WHITEHALL-II, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, education, Alleles, METAANALYSIS, 030304 developmental biology, Aged, business.industry, Gene Expression Profiling, Membrane Proteins, Reproducibility of Results, Odds ratio, medicine.disease, Phosphoproteins, ROTTERDAM, CALCIFICATION, VASCULAR SMOOTH-MUSCLE, Minor allele frequency, Crk-Associated Substrate Protein, Intima-media thickness, Gene Expression Regulation, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Genetic Loci, business
Abstract: Background— Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results— To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT mean , IMT max , and IMT mean-max ), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1 ) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P =6.75×10 −7 for IMT max ; replication P =7.24×10 −6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort ( P =0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P =6.53×10 −6 , n=13 591; and 0.95 [0.92–0.98], P =1.83×10 −4 , n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions— This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.
Published: 2012

38. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Author: Sarah Edkins, Anubha Mahajan, Nita G. Forouhi, Danish Saleheen, Lori L. Bonnycastle, Jackie F. Price, Lu Qi, Jasmina Kravic, Laura J. Scott, Susanne Moebus, Timothy M. Frayling, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Lars Lind, James F. Wilson, John Beilby, Emil Rehnberg, Veikko Salomaa, Richard N. Bergman, Thomas Illig, Ruth J. F. Loos, Martina Müller-Nurasyid, Andrew Crenshaw, Karl-Heinz Jöckel, Krista Fischer, James B. Meigs, Rob M. van Dam, George Dedoussis, Christopher J. Groves, Julia Meyer, Valur Emilsson, Timo Saaristo, Kees Hovingh, Joseph Trakalo, Peter Kraft, André G. Uitterlinden, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Denis Rybin, Gonçalo R. Abecasis, Andrew T. Hattersley, Sonia Shah, Bruna Gigante, Jaakko Tuomilehto, Pierre Fontanillas, Kay-Tee Khaw, Annette Peters, Andrew D. Johnson, Rafn Benediktsson, Candace Guiducci, Andrew P. Morris, Tõnu Esko, Bo Isomaa, Anne U. Jackson, Beverley Balkau, Peter Donnelly, Thomas W. Mühleisen, Barbara Thorand, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Roman Wennauer, Karl Gertow, Wen Hong L. Kao, Alan James, Cordelia Langford, Christian Herder, Timo A. Lakka, Soumya Raychaudhuri, Jian'an Luan, Katharine R. Owen, Jennie Hui, Francis S. Collins, Juha Saltevo, David Couper, Bernhard O. Boehm, Sonali Pechlivanis, Raimund Erbel, Suthesh Sivapalaratnam, Markku Laakso, Augustine Kong, Heather M. Stringham, Leena Kinnunen, Kathleen Stirrups, Markus M. Nöthen, Ashok Kumar, Andrew R. Wood, Delilah Zabaneh, Rona J. Strawbridge, Bill Musk, Noël P. Burtt, Eeva Korpi-Hyövälti, Oddgeir L. Holmen, Inga Prokopenko, Marilyn C. Cornelis, Elodie Eury, Angela Silveira, Inês Barroso, Michael Roden, Unnur Thorsteinsdottir, Josée Dupuis, Han Chen, Cornelia M. van Duijn, Samuli Ripatti, Anna Jonsson, Gerald Steinbach, George B. Grant, Kristian Hveem, Andres Metspalu, Astradur B. Hreidarsson, Guillaume Charpentier, John Danesh, Claudia Langenberg, Sirkka Keinänen-Kiukaanniemi, Christian Dina, James S. Pankow, Panos Deloukas, Rainer Rauramaa, Satu Männistö, Kaarel Krjutškov, Eric Boerwinkle, Wendy Winckler, Valeriya Lyssenko, Anders Hamsten, Philippe Froguel, Nancy L. Pedersen, Harry Campbell, Sailaja Vedantam, Nicholas J. Wareham, Hassan Khan, Simon C. Potter, Damiano Baldassarre, Tiinamaija Tuomi, Vasiliki Lagou, Mozhgan Dorkhan, Stavroula Kanoni, Benjamin F. Voight, Wolfgang Rathmann, Tanya M. Teslovich, Antigone S. Dimas, Bengt Sennblad, Olle Melander, Albert Hofman, Mark I. McCarthy, Andrew D. Morris, Fabrizio Veglia, Karen L. Mohlke, Melissa Parkin, Sarah E. Hunt, Frank B. Hu, Elena Tremoli, Gudmar Thorleifsson, Steve E. Humphries, Jason Carey, Eero Lindholm, Alex S. F. Doney, Peter Almgren, Erik Ingelsson, Colin N. A. Palmer, Johanna Kuusisto, Inger Njølstad, Ann-Christine Syvänen, Leena Peltonen, Eric J.G. Sijbrands, Ross M. Fraser, Mieke D. Trip, Ghazala Mirza, Robert W. Lawrence, Neil Robertson, David Altshuler, Harald Grallert, Gunnar Sigurðsson, Kari Stefansson, N. William Rayner, Johan G. Eriksson, Christian Gieger, Emmi Tikkanen, Mustafa Atalay, S Wiltshire, Eleftheria Zeggini, Alena Stančáková, Loukianos S. Rallidis, Jouko Saramies, Stéphane Lobbens, Man Li, Hyun Min Kang, Loic Yengo, Norman Klopp, Ayellet V. Segrè, Carl G. P. Platou, Tom Forsén, Qi Sun, Karin Leander, Caroline S. Fox, Sekar Kathiresan, Jose C. Florez, Leif Groop, Teresa Ferreira, John R. B. Perry, Ulf de Faire, Peter S. Chines, Elizabeth J. Rossin, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Surgery, Dermatology, Epidemiology, and Internal Medicine
Subjects: Male, Linkage disequilibrium, Medizin, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, Pakistan, Gene, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, medicine.disease, Genetic architecture, 3. Good health, Diabetes Mellitus, Type 2, Genes, Evolutionary biology, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

39. Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts

Author: Gerry Fowkes, Aroon D. Hingorani, Tina Shah, KaWah Li, Marlene C. W. Stewart, Juan-Pablo Casas, Meena Kumari, Claudia Lamina, Theodore Papamarkou, Philippa J. Talmud, Steve E. Humphries, John C. Whittaker, Delilah Zabaneh, Jutta Palmen, Monika Summerer, Jackie F. Price, Jemma C. Hopewell, Nick Wainwright, Sonia Shah, Mika Kivimäki, Bernhard Paulweber, Fotios Drenos, Robert Clarke, Florian Kronenberg, Nicholas J. Wareham, and M. S. Sandhu
Subjects: Adult, Male, Candidate gene, Genotype, Population, Single-nucleotide polymorphism, Locus (genetics), Polymorphism, Single Nucleotide, Article, White People, Cohort Studies, SNP, Humans, education, Genetic Association Studies, Genetic association, Aged, Oligonucleotide Array Sequence Analysis, Genetics, education.field_of_study, biology, Lipoprotein(a), Middle Aged, Europe, Phenotype, Genetic Loci, biology.protein, Chromosomes, Human, Pair 6, Female, Cardiology and Cardiovascular Medicine
Abstract: Background: Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels. Methods: 48,032 single nucleotide polymorphisms (SNPs) from the Illumina HumanCVD BeadChip were genotyped in 5059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p
Published: 2011

40. Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip

Author: Delilah, Zabaneh, Tom R, Gaunt, Meena, Kumari, Fotios, Drenos, Sonia, Shah, Diane, Berry, Chris, Power, Elina, Hypponen, Tina, Shah, Jutta, Palmen, Jacky, Pallas, Philippa J, Talmud, Juan Pablo, Casas, Reecha, Sofat, Gordon, Lowe, Ann, Rumley, Richard W, Morris, Peter H, Whincup, Santiago, Rodriguez, Shah, Ebrahim, Michael G, Marmot, George Davey, Smith, Debbie A, Lawlor, Mika, Kivimaki, John, Whittaker, Aroon D, Hingorani, Ian N, Day, and Steve E, Humphries
Subjects: Male, Genetic Techniques, Genotype, Meta-Analysis as Topic, Population Surveillance, von Willebrand Factor, Humans, Female, Middle Aged, Polymorphism, Single Nucleotide, ABO Blood-Group System
Abstract: We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.
Published: 2011

41. Genome-wide linkage scan on estimated breeding values for a quantitative trait

Author: Ian Mackay and Delilah Zabaneh
Subjects: Male, lcsh:QH426-470, Genetic Linkage, Pedigree information, Quantitative trait locus, Biology, Cohort Studies, Quantitative Trait, Heritable, Genetic linkage, Genetics, medicine, Humans, Computer Simulation, Genetics(clinical), Genetic Testing, Longitudinal Studies, Triglycerides, Genetics (clinical), Genome wide linkage, Genetic testing, Linkage (software), Models, Genetic, medicine.diagnostic_test, Genome, Human, Chromosome Mapping, Fasting, Replicate, Pedigree, lcsh:Genetics, Phenotype, Proceedings, Evolutionary biology, Trait, Chromosomes, Human, Pair 5, Female, Lod Score, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 7
Abstract: Background A genome-wide linkage scan was performed on Replicate 1 of the simulated data for fasting triglyceride levels. The aim of this study was to implement mixed-model methodology to estimate breeding values for each individual for this trait and to assess the merit of these breeding values in linkage analysis. These breeding values utilize all the pedigree information, and the genetic and phenotypic correlations with other measured traits across the two cohorts. A genome-wide linkage scan was run on both the new breeding value traits and the original traits. Results Using breeding values, a maximum LOD of 7.78 was found on chromosome 5 at a position very close to a gene underlying the triglyceride levels. This effect was not detected using the original trait. Conclusion The results imply that estimating breeding values may be a suitable method of deriving traits for use in genome-wide scans.
Published: 2003

42. A gene-centric study of common carotid artery remodelling

Author: Seamus C. Harrison, Ann-Christine Syvänen, Aroon D. Hingorani, Obi Agu, Jan D. Blankensteijn, Anders Hamsten, Rona J. Strawbridge, Gert J. de Borst, Ulf de Faire, Lasse Folkersen, Gerry Fowkes, Mika Kivimäki, Karl Gertow, Elena Tremoli, Ionna Tzoulaki, Kristiina Nyyssönen, John E. Deanfield, Sonia Shah, Delilah Zabaneh, Fabrizio Veglia, Folkert W. Asselbergs, Andre M. van Rij, Bengt Sennblad, Philippa J. Talmud, Steve E. Humphries, Sita H. Vermeulen, Matthew J. Bown, Rainer Rauramaa, Suzanne Holewijn, Anders Franco-Cereceda, Gregory T. Jones, Jacqueline F. Price, Andries J. Smit, Per-Olof Eriksson, Annette F. Baas, Elmo Mannarino, Damiano Baldassarre, Nicholas J. Wareham, Philippe Giral, Meena Kumari, Yolanda van der Graaf, Bruna Gigante, Fotios Drenos, Jacqueline de Graaf, Angela Silveira, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Surgery, and ICaR - Ischemia and repair
Subjects: Male, Vascular remodelling, Pathology, Genome-wide association study, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, INTIMA-MEDIA THICKNESS, Genome-wide association studies, 0302 clinical medicine, Medicine, Common carotid artery, RISK, 0303 health sciences, Middle Aged, Phenotype, Chromosomes, Human, Pair 1, CARDIOVASCULAR-DISEASE, 2ND MANIFESTATIONS, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Carotid Artery, Common, Polymorphism, Single Nucleotide, Article, Vascular remodelling in the embryo, 03 medical and health sciences, medicine.artery, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, Genetic Association Studies, Health aging / healthy living Cardiovascular diseases [IGMD 5], METAANALYSIS, 030304 developmental biology, Aged, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], ABDOMINAL AORTIC-ANEURYSM, business.industry, DIAMETER, Carotid artery.common, Blood pressure, Intima-media thickness, ATHEROSCLEROSIS, Abdominal aortic aneurysm, business, Expansive, Carotid artery, Aortic Aneurysm, Abdominal
Abstract: Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development., Highlights ► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
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43. Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies

Author: Fotios Drenos, Meena Kumari, Delilah Zabaneh, George Davey Smith, Juan P. Casas, Ian N. M. Day, John C. Whittaker, Reecha Sofat, Tom R. Gaunt, Philippa J. Talmud, Steve E. Humphries, Sonia Shah, Mika Kivimäki, Jutta Palmen, Tina Shah, Daniel I. Swerdlow, Debbie A Lawlor, Shah Ebrahim, Jackie A. Cooper, and Aroon D. Hingorani
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Heart disease, Blood lipids, Coronary Disease, Hyperlipidemias, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Clinical Research, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Triglycerides, Aged, Hypolipidemic Agents, Framingham Risk Score, Cholesterol, business.industry, Cholesterol, HDL, Cholesterol, LDL, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Phenotype, Endocrinology, chemistry, Cardiovascular Diseases, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business
Abstract: Aims The aim of this study was to quantify the collective effect of common lipid-associated single nucleotide polymorphisms (SNPs) on blood lipid levels, cardiovascular risk, use of lipid-lowering medication, and risk of coronary heart disease (CHD) events. Methods and results Analysis was performed in two prospective cohorts: Whitehall II (WHII; N = 5059) and the British Women’s Heart and Health Study (BWHHS; N = 3414). For each participant, scores were calculated based on the cumulative effect of multiple genetic variants influencing total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Compared with the bottom quintile, individuals in the top quintile of the LDL-C genetic score distribution had higher LDL-C {mean difference of 0.85 [95% confidence interval, (CI) = 0.76–0.94] and 0.63 [95% CI = 0.50–0.76] mmol/l in WHII and BWHHS, respectively}. They also tended to have greater odds of having ‘high-risk’ status (Framingham 10-year cardiovascular disease risk >20%) [WHII: odds ratio (OR) = 1.36 (0.93–1.98), BWHHS: OR = 1.49 (1.14–1.94)]; receiving lipid-lowering treatment [WHII: OR = 2.38 (1.57–3.59), BWHHS: OR = 2.24 (1.52–3.29)]; and CHD events [WHII: OR = 1.43 (1.02–2.00), BWHHS: OR = 1.31 (0.99–1.72)]. Similar associations were observed for the TC score in both studies. The TG score was associated with high-risk status and medication use in both studies. Neither HDL nor TG scores were associated with the risk of coronary events. The genetic scores did not improve discrimination over the Framingham risk score. Conclusion At the population level, common SNPs associated with LDL-C and TC contribute to blood lipid variation, cardiovascular risk, use of lipid-lowering medications and coronary events. However, their effects are too small to discriminate future lipid-lowering medication requirements or coronary events.
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44. Phenome-wide analysis of genome-wide polygenic scores

Author: Kaili Rimfeld, Paul F. O'Reilly, Delilah Zabaneh, Eva Krapohl, Pingault J, Jack Euesden, S. von Stumm, Gerome Breen, Robert Plomin, and Philip S. Dale
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, Adolescent, BF Psychology, media_common.quotation_subject, Intelligence, education, QH426 Genetics, Phenome, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Personality, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetic Association Studies, media_common, Behavior, business.industry, Depression, Cognition, Explained variation, United Kingdom, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Behavioral medicine, Predictive power, Global Positioning System, Schizophrenia, Female, Original Article, Psychology, business, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Psychopathology, Clinical psychology, Forecasting, Genome-Wide Association Study
Abstract: Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents’ behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development.

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