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1. A fast wavelet-based functional association analysis replicates several susceptibility loci for birth weight in a Norwegian population

Author: William R. P. Denault, Julia Romanowska, Øyvind Helgeland, Bo Jacobsson, Håkon K. Gjessing, and Astanand Jugessur
Subjects: Association analysis, GWAS, Wavelet, Birth weight, Polygenic trait, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Birth weight (BW) is one of the most widely studied anthropometric traits in humans because of its role in various adult-onset diseases. The number of loci associated with BW has increased dramatically since the advent of whole-genome screening approaches such as genome-wide association studies (GWASes) and meta-analyses of GWASes (GWAMAs). To further contribute to elucidating the genetic architecture of BW, we analyzed a genotyped Norwegian dataset with information on child’s BW (N=9,063) using a slightly modified version of a wavelet-based method by Shim and Stephens (2015) called WaveQTL. Results WaveQTL uses wavelet regression for regional testing and offers a more flexible functional modeling framework compared to conventional GWAS methods. To further improve WaveQTL, we added a novel feature termed “zooming strategy” to enhance the detection of associations in typically small regions. The modified WaveQTL replicated five out of the 133 loci previously identified by the largest GWAMA of BW to date by Warrington et al. (2019), even though our sample size was 26 times smaller than that study and 18 times smaller than the second largest GWAMA of BW by Horikoshi et al. (2016). In addition, the modified WaveQTL performed better in regions of high LD between SNPs. Conclusions This study is the first adaptation of the original WaveQTL method to the analysis of genome-wide genotypic data. Our results highlight the utility of the modified WaveQTL as a complementary tool for identifying loci that might escape detection by conventional genome-wide screening methods due to power issues. An attractive application of the modified WaveQTL would be to select traits from various public GWAS repositories to investigate whether they might benefit from a second analysis.
Published: 2021
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2. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

Author: Suzanne Vogelezang, Jonathan P Bradfield, Tarunveer S Ahluwalia, John A Curtin, Timo A Lakka, Niels Grarup, Markus Scholz, Peter J van der Most, Claire Monnereau, Evie Stergiakouli, Anni Heiskala, Momoko Horikoshi, Iryna O Fedko, Natalia Vilor-Tejedor, Diana L Cousminer, Marie Standl, Carol A Wang, Jorma Viikari, Frank Geller, Carmen Íñiguez, Niina Pitkänen, Alessandra Chesi, Jonas Bacelis, Loic Yengo, Maties Torrent, Ioanna Ntalla, Øyvind Helgeland, Saskia Selzam, Judith M Vonk, Mohammed H Zafarmand, Barbara Heude, Ismaa Sadaf Farooqi, Akram Alyass, Robin N Beaumont, Christian T Have, Peter Rzehak, Jose Ramon Bilbao, Theresia M Schnurr, Inês Barroso, Klaus Bønnelykke, Lawrence J Beilin, Lisbeth Carstensen, Marie-Aline Charles, Bo Chawes, Karine Clément, Ricardo Closa-Monasterolo, Adnan Custovic, Johan G Eriksson, Joaquin Escribano, Maria Groen-Blokhuis, Veit Grote, Dariusz Gruszfeld, Hakon Hakonarson, Torben Hansen, Andrew T Hattersley, Mette Hollensted, Jouke-Jan Hottenga, Elina Hyppönen, Stefan Johansson, Raimo Joro, Mika Kähönen, Ville Karhunen, Wieland Kiess, Bridget A Knight, Berthold Koletzko, Andreas Kühnapfel, Kathrin Landgraf, Jean-Paul Langhendries, Terho Lehtimäki, Jaakko T Leinonen, Aihuali Li, Virpi Lindi, Estelle Lowry, Mariona Bustamante, Carolina Medina-Gomez, Mads Melbye, Kim F Michaelsen, Camilla S Morgen, Trevor A Mori, Tenna R H Nielsen, Harri Niinikoski, Albertine J Oldehinkel, Katja Pahkala, Kalliope Panoutsopoulou, Oluf Pedersen, Craig E Pennell, Christine Power, Sijmen A Reijneveld, Fernando Rivadeneira, Angela Simpson, Peter D Sly, Jakob Stokholm, Kook K Teo, Elisabeth Thiering, Nicholas J Timpson, André G Uitterlinden, Catharina E M van Beijsterveldt, Barbera D C van Schaik, Marc Vaudel, Elvira Verduci, Rebecca K Vinding, Mandy Vogel, Eleftheria Zeggini, Sylvain Sebert, Mads V Lind, Christopher D Brown, Loreto Santa-Marina, Eva Reischl, Christine Frithioff-Bøjsøe, David Meyre, Eleanor Wheeler, Ken Ong, Ellen A Nohr, Tanja G M Vrijkotte, Gerard H Koppelman, Robert Plomin, Pål R Njølstad, George D Dedoussis, Philippe Froguel, Thorkild I A Sørensen, Bo Jacobsson, Rachel M Freathy, Babette S Zemel, Olli Raitakari, Martine Vrijheid, Bjarke Feenstra, Leo-Pekka Lyytikäinen, Harold Snieder, Holger Kirsten, Patrick G Holt, Joachim Heinrich, Elisabeth Widén, Jordi Sunyer, Dorret I Boomsma, Marjo-Riitta Järvelin, Antje Körner, George Davey Smith, Jens-Christian Holm, Mustafa Atalay, Clare Murray, Hans Bisgaard, Mark I McCarthy, Early Growth Genetics Consortium, Vincent W V Jaddoe, Struan F A Grant, and Janine F Felix
Subjects: Genetics, QH426-470
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values
Published: 2020
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3. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents

Author: Dinka Smajlagic, Ksenia Lavrichenko, Pål R. Njølstad, Gun Peggy Knudsen, Siren Berland, Marc Vaudel, Stefan Johansson, Per M. Knappskog, Øyvind Helgeland, Jan Haavik, and Gunnar Houge
Subjects: Adult, Male, DNA Copy Number Variations, Population, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, mental disorders, Gene duplication, Genetics, Humans, Copy-number variation, education, Allele frequency, Genetics (clinical), Sequence Deletion, 030304 developmental biology, 0303 health sciences, education.field_of_study, Neurodevelopmental disorders, Medical genetics, Infant, Newborn, Inheritance (genetic algorithm), Genomics, Penetrance, Pedigree, Neurodevelopmental delay, Female, 030217 neurology & neurosurgery, Cohort study
Abstract: Recurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking. Here we perform array-based CNV calling in 12,252 mother–father–child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions. We estimate the total prevalence of recurrent NDD CNVs (duplications and deletions) in live-born children to 0.48% (95% C.I.: 0.37–0.62%), i.e., ~1 in 200 newborns has either a deletion or duplication in these NDDs associated regions. Approximately a third of the newborn recurrent NDD CNVs (34%, N = 20/59) are de novo variants. We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~1:12,000). In conclusion, our analysis of an unselected and representative population of newborns and their parents provides a clearer picture of the rate of recurrent microdeletions/duplications implicated in neurodevelopmental delay. These results will provide an important resource for genetic diagnostics and counseling.
Published: 2020

4. 399The causal effect of BMI on neurodevelopment: a within family Mendelian randomization study using MoBa

Author: Ragna Bugge Askeland, Laura D Howe, Per Magnus, Ziada Ayorech, Ted Reichborn-Kjennerud, Alexandra Havdahl, Helga Ask, Tim T Morris, Amanda Hughes, George Davey Smith, Øyvind Helgeland, Stefan Johansson, Martin Steen Tesli, Pål R. Njølstad, Ole A. Andreassen, and Neil M Davies
Subjects: Genetics, Epidemiology, Mendelian randomization, Causal effect, General Medicine, Biology
Abstract: Background Higher BMI in childhood predicts subsequent neurodevelopmental and emotional problems, but it is unclear if associations are causal. Observational studies are vulnerable to reverse causation and confounding. Mendelian randomization (MR) studies with unrelated individuals can also suffer from familial biases, such as dynastic effects (“genetic nurture”). Methods We apply within-family MR (WFMR) to overcome these biases. We used genetic information from 26,370 family trios in the Norwegian Mother, Father and Child Cohort Study (MoBa) to construct BMI polygenic scores in children and both parents. By using all three polygenic scores to instrument BMI, we avoided familial biases affecting previous studies. Results Multivariable-adjusted and conventional MR models implied an impact of children’s BMI on depressive, ADHD, and autism symptoms. In conventional MR models, a 5kg/m2 increase in BMI corresponded to depressive symptoms 0.49 SD higher (95%CI: 0.24-0.73), and ADHD symptoms 0.49 SD higher (95%CI: 0.28-0.70). WFMR estimates were less precise but gave little evidence of causal impacts of children’s BMI. Maternal BMI was positively associated with children’s depressive (0.16 SD per 5kg/m2, 95%CI: 0.04-0.28) and autism symptoms, and paternal BMI with children’s ADHD symptoms. Conclusions Compared to conventional MR models, MR models accounting for parental genotype found less evidence of causal effects of children’s own BMI on emotional and neurodevelopmental symptoms. The discrepancy may suggest an influence of family or population-level effects. Key messages The influence of children’s own BMI on emotional and neurodevelopmental problems may have been overstated. Parental BMI, familial or population level effects may influence these outcomes.
Published: 2021

5. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Maria Carolina Borges, M. Geoffrey Hayes, Ke Hao, Carol A. Wang, Marjo-Riitta Järvelin, Niina Pitkänen, Ilkka Kalliala, Mariona Bustamante, Olli T. Raitakari, Bridget A. Knight, Robin N Beaumont, Matthew T. Weirauch, Line Skotte, Matthias Wielscher, Mark I. McCarthy, Klaus Bønnelykke, Vincent W. V. Jaddoe, Elina Hyppönen, Ole Mors, Tarunveer S. Ahluwalia, Thomas Werge, Frank Geller, Jonathan P. Bradfield, Vivek Appadurai, Kristin Skogstrand, Merete Nordentoft, Suzanne Vogelezang, Preben Bo Mortensen, Xueping Liu, Daniel Miller, Hakon Hakonarson, João Fadista, Pål R. Njølstad, Leah C. Kottyan, Wesley K. Thompson, Bruce Bedell, Katja Pahkala, Stefan Johansson, Dorte Helenius, Louis J. Muglia, Janine F. Felix, Rachel M. Freathy, Heather A. Boyd, Bjarke Feenstra, Ge Zhang, Anubha Mahajan, Alfonso Buil, Bo Jacobsson, Martine Vrijheid, Frederick T.J. Lin, William L. Lowe, Mads Melbye, Ron Nudel, Denise M. Scholtens, Julius Juodakis, Shouneng Peng, Christine Power, Andrew J. Schork, Jeffrey C. Murray, David M. Hougaard, Craig E. Pennell, Øyvind Helgeland, Struan F.A. Grant, Kelli K. Ryckman, Mary L. Marazita, Xiaoting Chen, Jonas Bacelis, Anders D. Børglum, Debbie A Lawlor, Hans Bisgaard, Robert M. Rossi, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Clinicum, Helsinki University Hospital Area, Epidemiology, Internal Medicine, Pediatrics, Erasmus MC other, Liu, Xueping, Helenius, Dorte, Skotte, Line, Beaumont, Robin N, Hyppönen, Elina, Feenstra, Bjarke, and UNIVERSITY OF OULU
Subjects: 0301 basic medicine, LD SCORE REGRESSION, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Reproductive health and childbirth, Bioinformatics, Low Birth Weight and Health of the Newborn, Genome-wide association studies, 3123 Gynaecology and paediatrics, Pregnancy, Genotype, Infant Mortality, Genetics research, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, GWAS, FUNCTIONAL VARIATION, Aetiology, lcsh:Science, Pediatric, Multidisciplinary, Genome, Gestational age, Single Nucleotide, 021001 nanoscience & nanotechnology, 3. Good health, Multidisciplinary Sciences, Chromosomes, Human, Pair 2, Pair 2, Gestation, Science & Technology - Other Topics, Premature Birth, Cytokines, Female, 0210 nano-technology, Human, Reproductive signs and symptoms, EXPRESSION, PRETERM BIRTH, Science, Reproductive biology, Locus (genetics), Gestational Age, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, General Biochemistry, Genetics and Molecular Biology, Chromosomes, 03 medical and health sciences, AGE, Fetus, Preterm, medicine, Genetics, SNP, Humans, Polymorphism, Science & Technology, Genome, Human, Human Genome, Infant, Newborn, Infant, General Chemistry, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, Newborn, 030104 developmental biology, Good Health and Well Being, lcsh:Q, WEIGHT, 3111 Biomedicine, HAPLOTYPES, Genome-Wide Association Study
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality., Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.
Published: 2019

6. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author: Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology
Subjects: Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.
Published: 2022

7. The genetic architecture of sporadic and multiple consecutive miscarriage

Author: Avinash Ramu, Ole Mors, Cecilia M. Lindgren, Scott D. Gordon, Harold Snieder, Kuang Lin, Jenny C Censin, Dale R. Nyholt, Maarja Lepamets, Samantha Laber, Andres Salumets, Siyang Liu, Ana Luiza Gonçalves Soares, Stefan Johansson, Nicholas G. Martin, Jodie N. Painter, Xin Jin, Christiana Kartsonaki, Viktorija Kukushkina, Christian M. Becker, Zhengming Chen, Andrew P. Morris, Preben Bo Mortensen, Rasmus Nielsen, Robin G Walters, Sarah E. Medland, Øyvind Helgeland, Chia-Yen Chen, Julius Juodakis, Stephanie B. Seminara, Benjamin M. Neale, Marianne Andersen, Penelope A. Lind, Ingrid Granne, Donald F. Conrad, Reedik Mägi, Jonas Bybjerg-Grauholm, Margaret F. Lippincott, Jonas Bacelis, Debbie A Lawlor, Anders D. Børglum, Pål R. Njølstad, Ling Yang, Andres Metspalu, Triin Laisk, Bo Jacobsson, Krina T. Zondervan, Liming Li, Grant W. Montgomery, Thomas Werge, David M. Hougaard, J Southcombe, Merete Nordentoft, Iona Y Millwood, Teresa Ferreira, Life Course Epidemiology (LCE), HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, and Institute for Molecular Medicine Finland
Subjects: 0301 basic medicine, Placenta, Inheritance Patterns, Datasets as Topic, General Physics and Astronomy, Genome-wide association study, VARIANTS, Genome-wide association studies, Miscarriage, 0302 clinical medicine, Gene Frequency, PREGNANCY LOSS, Pregnancy, 3123 Gynaecology and paediatrics, 2.1 Biological and endogenous factors, TERMINOLOGY, Aetiology, Medical History Taking, RISK, 030219 obstetrics & reproductive medicine, Multidisciplinary, STILLBIRTH, Obstetrics, 1184 Genetics, developmental biology, physiology, Single Nucleotide, Middle Aged, 3. Good health, MENDELIAN RANDOMIZATION, Female, Adult, Abortion, Habitual, medicine.medical_specialty, Science, Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Mendelian randomization, REGRESSION, Genetics, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Allele frequency, METAANALYSIS, Aged, Genetic association, Whites, business.industry, Spontaneous, Contraception/Reproduction, Human Genome, Abortion, General Chemistry, Odds ratio, medicine.disease, Habitual, Abortion, Spontaneous, Minor allele frequency, BODY-MASS INDEX, Good Health and Well Being, 030104 developmental biology, Case-Control Studies, Infertility, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication., Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.
Published: 2020

8. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Author: Inês Barroso, Peter D. Sly, Jose Ramon Bilbao, Nicholas J. Timpson, Johan G. Eriksson, Maria M. Groen-Blokhuis, Sijmen A. Reijneveld, Dariusz Gruszfeld, George Davey Smith, Christine Power, Eva Reischl, Mandy Vogel, Andrew T. Hattersley, Øyvind Helgeland, Niina Pitkänen, Akram Alyass, Jean-Paul Langhendries, Elina Hyppönen, Kathrin Landgraf, Loreto Santa-Marina, Frank Geller, Christopher D. Brown, Elvira Verduci, Katja Pahkala, Olli T. Raitakari, Joaquin Escribano, Torben Hansen, Hakon Hakonarson, Barbara Heude, Bridget A. Knight, Maties Torrent, Robin N Beaumont, Judith M. Vonk, Estelle Lowry, Patrick G. Holt, Harold Snieder, Carol A. Wang, Mark I. McCarthy, Christine Frithioff-Bøjsøe, Tanja G. M. Vrijkotte, Natalia Vilor-Tejedor, Lisbeth Carstensen, Catharina E. M. van Beijsterveldt, Ville Karhunen, Virpi Lindi, Marjo-Riitta Järvelin, Tarunveer S. Ahluwalia, Jordi Sunyer, Jaakko T. Leinonen, Clare S. Murray, Klaus Bønnelykke, Thorkild I. A. Sørensen, André G. Uitterlinden, Janine F. Felix, John A. Curtin, Mika Kähönen, Jorma Viikari, Leo-Pekka Lyytikäinen, Oluf Pedersen, Carmen Iñiguez, Harri Niinikoski, Wieland Kiess, Kim F. Michaelsen, Evie Stergiakouli, Anni Heiskala, Alessandra Chesi, Craig E. Pennell, Mohammed H Zafarmand, Peter Rzehak, Kook K Teo, Aihuali Li, Marie Standl, Veit Grote, Momoko Horikoshi, Ellen A. Nohr, Eleanor Wheeler, Rachel M. Freathy, Iryna O. Fedko, Gerard H. Koppelman, Elisabeth Widen, Jens-Christian Holm, Raimo Joro, David Meyre, Mustafa Atalay, Theresia M. Schnurr, Camilla Schmidt Morgen, Adnan Custovic, Niels Grarup, Trevor A. Mori, Terho Lehtimäki, Christian Theil Have, Angela Simpson, Mads Melbye, Bjarke Feenstra, Lawrence J. Beilin, Stefan Johansson, Ioanna Ntalla, Martine Vrijheid, Mariona Bustamante, George Dedoussis, Sylvain Sebert, Jonas Bacelis, Carolina Medina-Gomez, Elisabeth Thiering, Ken K. Ong, Eleftheria Zeggini, Berthold Koletzko, Karine Clément, Bo L. Chawes, Mette Hollensted, Babette S. Zemel, Markus Scholz, Holger Kirsten, Antje Körner, Albertine J. Oldehinkel, Barbera D. C. van Schaik, Philippe Froguel, Vincent W. V. Jaddoe, Dorret I. Boomsma, Struan F.A. Grant, Loic Yengo, Jonathan P. Bradfield, Tenna Ruest Haarmark Nielsen, Suzanne Vogelezang, Jakob Stokholm, Pål R. Njølstad, Bo Jacobsson, Marc Vaudel, Peter J. van der Most, Andreas Kühnapfel, Mads Vendelbo Lind, Timo A. Lakka, Saskia Selzam, Robert Plomin, Marie-Aline Charles, Jouke-Jan Hottenga, Kalliope Panoutsopoulou, Fernando Rivadeneira, Rebecca K. Vinding, Hans Bisgaard, I. S. Farooqi, Joachim Heinrich, Diana L. Cousminer, Ricardo Closa-Monasterolo, Claire Monnereau, European Commission, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, APH - Global Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, ARD - Amsterdam Reproduction and Development, APH - Methodology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Children’s Hospital of Philadelphia (CHOP ), Herlev and Gentofte Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], University of Kuopio, University of Copenhagen = Københavns Universitet (KU), Universität Leipzig [Leipzig], University Medical Center Groningen [Groningen] (UMCG), University of Bristol [Bristol], Université d'Oulu, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Vrije Universiteit Brussel (VUB), CIBER de Epidemiología y Salud Pública (CIBERESP), Helmholtz-Zentrum München (HZM), University of Newcastle [Australia] (UoN), Turku University Hospital (TYKS), Statens Serum Institut [Copenhagen], Sahlgrenska Academy at University of Gothenburg [Göteborg], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Queen Mary University of London (QMUL), Norwegian Institute of Public Health [Oslo] (NIPH), King‘s College London, University of Groningen [Groningen], University of Amsterdam [Amsterdam] (UvA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Cambridge [UK] (CAM), McMaster University [Hamilton, Ontario], University of Exeter, Ludwig-Maximilians-Universität München (LMU), University of the Basque Country [Bizkaia] (UPV/EHU), The Wellcome Trust Sanger Institute [Cambridge], The University of Western Australia (UWA), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universitat Rovira i Virgili, Imperial College London, University of Helsinki, Vrije Universiteit Amsterdam [Amsterdam] (VU), University College of London [London] (UCL), University of Bergen (UiB), University of Tampere [Finland], University of Oulu, Copenhagen University Hospital, University of Turku, University of Queensland [Brisbane], Haukeland University Hospital, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust University College London Wellcome 090532106130098381203141212259WT206194United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)U01DK105535National Institute for Health Research (NIHR)NF-SI-0617-10090Netherlands Organization for Health Research and DevelopmentTOP 40-00812-9811010American Diabetes Association1-17-PDF-077Daniel B. Burke Chair for Diabetes Research United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USAR01 HD058886Agencia de Gestio D'Ajuts Universitaris de Recerca Agaur (AGAUR)2017 FI_B 00636Generalitat de Catalunya -Fons Social Europeu European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG) 322605Oak Foundation Fellowship Wellcome TrustEuropean CommissionWT104150098497/Z/12/ZRoyal Society of LondonEuropean CommissionWT104150Wellcome Trust098395/Z/12/ZNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs Finnish Cultural Foundation KNAW Academy Professor Award PAH/6635TARGET Danish Diabetes Academy Copenhagen Graduate School of Health and Medical Sciences Netherlands Organization for Health Research and Development (VIDI) 016.136.361European Research Council (ERC)European Commission648916European Research Council (ERC)European Commission UK Research & Innovation (UKRI)Medical Research Council UK (MRC)European CommissionMRC_MC_UU_12012/5MC_UU_00011/1National Institute for Health Research (NIHR) Botnar Foundation Bernard Wolfe Health Neuroscience Endowment European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO 279153University of Bristol UK Research & Innovation (UKRI)Medical Research Council UK (MRC)MC_UU_00011/1MC_UU_00011/3French National Agency of Research, F-CRIN/FORCE, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Genomics of Sex Differences, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University of Copenhagen = Københavns Universitet (UCPH), Universität Leipzig, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, University of Newcastle [Callaghan, Australia] (UoN), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Felix, Janine F [0000-0002-9801-5774], Apollo - University of Cambridge Repository, Biological Psychology, APH - Mental Health, Felix, Janine F. [0000-0002-9801-5774], Tampere University, Tampere University Hospital Catchment Area, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Life Course Epidemiology (LCE), Vogelezang, Suzanne, Bradfield, Jonathan P, Ahluwalia, Tarunveer S, Curtin, John A, Hyppönen, Elina, Felix, JF, and Early Growth Genetics Consortium
Subjects: Male, Genetic-variation, Nedd4 Ubiquitin Protein Ligases, Pooled Analysis, Blood Pressure, 0302 clinical medicine, Human genetics, Mendelian Randomization, Young adult, Child, health care economics and organizations, Body mass index, Adiposity, Genetics & Heredity, 0303 health sciences, Statistics, 1184 Genetics, developmental biology, physiology, Genomics, adulto, 3. Good health, Cardiovascular Diseases, Child, Preschool, Physical Sciences, Menarche, genetic-variation, presión sanguínea, Monosaccharide Transport Proteins, Genetic loci, education, enfermedades cardiovasculares, Prostate-specific Antigen, Genetic correlation, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Genetics, Humans, prostate-specific antigen, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, childhood, 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Early Growth Genetics Consortium, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Single nucleotide polymorphisms, Mendelian Randomization Analysis, Biological Tissue, Diabetes Mellitus, Type 2, estudio de asociación genómica completa, genetic factors, mendelian randomization, análisis de la aleatorización mendeliana, proteínas de transporte de monosacáridos, 030217 neurology & neurosurgery, Mathematics, Demography, Developmental Biology, Cardiovascular Risk, Cancer Research, obesity, Physiology, humanos, adolescente, Overweight, QH426-470, Genome-wide association studies, Waist–hip ratio, Mathematical and Statistical Techniques, Medicine and Health Sciences, body mass index (BMI), Genetics of disease, Genetics (clinical), 2. Zero hunger, adiposity, Metaanalysis, Physiological Parameters, Connective Tissue, Female, medicine.symptom, Anatomy, pooled analysis, Life Sciences & Biomedicine, Research Article, Adult, cardiovascular risk, Adolescent, Birth weight, menarquia, Adipose tissue, Biology, 3121 Internal medicine, Research and Analysis Methods, medicine, overweight, Genetic Predisposition to Disease, Obesity, 030304 developmental biology, Waist-Hip Ratio, índice de masa corporal, Body Weight, Cardiometabolic Risk Factors, predisposición genética a la enfermedad, Heritability, Genome Analysis, young-adults, Genome-wide Association, índice cintura-cadera, Young-adults, genome-wide association, Genome-Wide Association Study
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.
Published: 2020

9. Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios

Author: Pol Solé-Navais, Ole A. Andreassen, Louis J. Muglia, Ge Zhang, Marc Vaudel, Dominika Modzelewska, Bo Jacobsson, Pål R. Njølstad, Jonas Bacelis, Øyvind Helgeland, Stefan Johansson, and Christopher Flatley
Subjects: Parents, AcademicSubjects/SCI01140, Offspring, Locus (genetics), Runs of Homozygosity, Biology, Polymorphism, Single Nucleotide, Correlation, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genotype, Genetics, Humans, Child, Association Studies Article, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Genome, Human, Norway, Homozygote, Chromosome Mapping, General Medicine, Genetics, Population, Genetic distance, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25,000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between −0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized parameters led to a ≃45% increase in the correlation between parental genetic relatedness and offspring ROH compared to using predefined parameters. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, using autozygosity mapping for common and rare autozygous segments, we identified three maternal loci in TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ≃2-5% (p-value< 2.3×10−6). We also found suggestive evidence of a fetal locus at 3q22.2, in the RYK gene region (p-value= 6.5×10−6). Autozygosity mapping may provide new insights on the genetic determinants and architecture of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.Author summaryMating between relatives has an effect on offspring’s health and fitness in a number of species. In the offspring of genetically related parents, this is translated into long segments of the genome in the homozygous form (the same copy is inherited from each parent), but there is no consensus on how long these segments must be. In this study, we used dense genetic data from parent-offspring trios to optimize the detection of long segments of the genome. Our optimized long homozygous segments increased the correlation between parental genetic relatedness and offspring runs of homozygosity by ≃45% compared to widely used parameters. Furthermore, while preterm delivery is the global leading cause of mortality in children under 5 years, the degree to which long homozygous segments affect human delivery timing is unknown. We observed no maternal, paternal nor fetal effects of the proportion of the genome covered by homozygous segments on time-to-spontaneous delivery. However, by mapping these segments to the genome, we found evidence supporting three specific maternal segments falling on TBC1D1, SIGLECs and EDN2 gene regions to be associated with lower time-to-spontaneous onset of delivery. Future studies should assess the functional impact of these genes on spontaneous onset of delivery.
Published: 2020

10. Introducing M-GCTA a Software Package to Estimate Maternal (or Paternal) Genetic Effects on Offspring Phenotypes

Author: David M. Evans, Jie Zheng, Marc Vaudel, George Davey Smith, Øyvind Helgeland, Pål R. Njølstad, Nicole M. Warrington, Zhen Qiao, and Stefan Johansson
Subjects: Male, Parents, 0301 basic medicine, Longitudinal study, Genotype, Offspring, Maternal effects, Birth weight, M-GCTA, Mothers, Biology, SNP heritability, Cohort Studies, Heritability, Fathers, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetics, Birth Weight, Humans, Computer Simulation, Longitudinal Studies, Child, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Models, Genetic, Maternal effect, Explained variation, Phenotype, 030104 developmental biology, Paternal Inheritance, Female, Maternal Inheritance, Paternal effects, Software, 030217 neurology & neurosurgery, G-REML, Forecasting, Genome-Wide Association Study
Abstract: There is increasing interest within the genetics community in estimating the relative contribution of parental genetic effects on offspring phenotypes. Here we describe the user-friendly M-GCTA software package used to estimate the proportion of phenotypic variance explained by maternal (or alternatively paternal) and offspring genotypes on offspring phenotypes. The tool requires large studies where genome-wide genotype data are available on mother- (or alternatively father-) offspring pairs. The software includes several options for data cleaning and quality control, including the ability to detect and automatically remove cryptically related pairs of individuals. It also allows users to construct genetic relationship matrices indexing genetic similarity across the genome between parents and offspring, enabling the estimation of variance explained by maternal (or alternatively paternal) and offspring genetic effects. We evaluated the performance of the software using a range of data simulations and estimated the computing time and memory requirements. We demonstrate the use of M-GCTA on previously analyzed birth weight data from two large population based birth cohorts, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother and Child Cohort Study (MoBa). We show how genetic variation in birth weight is predominantly explained by fetal genetic rather than maternal genetic sources of variation.
Published: 2020

11. Genome-Wide Association Study Links Autoimmune Addison’s Disease to Break of Central Tolerance

Author: Eirik Bratland, Daniel Eriksson, Ileana Ruxandra Botusan, Eystein S. Husebye, Alberto Falorni, Bergithe E. Oftedal, Stefan Johansson, Ellen C. Røyrvik, Haydee Artaza Alvarez, Per Dahlqvist, Anna-Lena Hulting, Jeanette Wahlberg Hughes, Åsa Hallgren, Lars Breivik, Nils Landegren, Olov Ekwall, Maribel Aranda Guillen, Anette S. B. Wolff, Anders Palmstrøm Jørgensen, Øyvind Helgeland, Sophie Bensing, Johan Svartberg, Olle Kämpe, Mark Vaudel, Amund Holte Berger, Sara Ström, Bjørn G. Nedrebø, Marianne Aardal Grytaas, Per M. Knappskog, and Kristian J. Fougner
Subjects: Genetics, Autoimmune Addison's Disease, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Central tolerance, Biology
Abstract: Autoimmune Addison’s disease is the predominant cause of primary adrenal failure, and is highly heritable. The genetic background has remained poorly understood due to the low prevalence and complex inheritance of the disease. We performed a genome-wide association study, which identified nine independent risk loci (P < 5 × 10–8). In addition to novel and previous risk loci involved in lymphocyte functionality, we further associated autoimmune Addison’s disease with two independent protein-coding alterations in the gene Autoimmune Regulator (AIRE). The most striking is the amino-acid substitution p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10–25), which introduces an additional cysteine residue in the zinc-finger motif of the PHD2 domain of AIRE. This unbiased elucidation of the genetic contribution to development of autoimmune Addison’s disease points to the importance of central immunological tolerance, and explains 35–41 percent of heritability.
Published: 2021

12. Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial)

Author: Grethe S. Tell, Eva Ringdal Pedersen, Klaus Meyer, Ottar Nygård, Jesse F. Gregory, Kjetil Halvorsen Løland, Gard Frodahl Tveitevåg Svingen, Yunpeng Ding, Øyvind Helgeland, and Per Magne Ueland
Subjects: Male, 0301 basic medicine, Time Factors, Myocardial Infarction, 030204 cardiovascular system & hematology, Coronary Angiography, Serine, Coronary artery disease, 0302 clinical medicine, Gene Frequency, Risk Factors, Myocardial infarction, Genetics (clinical), Norway, Homozygote, Middle Aged, Prognosis, Phenotype, Biochemistry, Female, Cardiology and Cardiovascular Medicine, Heterozygote, medicine.medical_specialty, Glycine, MTHFD1, Risk Assessment, Minor Histocompatibility Antigens, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Angina, Stable, Aged, Proportional Hazards Models, Methylenetetrahydrofolate Dehydrogenase (NADP), Polymorphism, Genetic, business.industry, Metabolism, medicine.disease, B vitamins, Logistic Models, 030104 developmental biology, Endocrinology, Methylenetetrahydrofolate dehydrogenase, Multivariate Analysis, Linear Models, business
Abstract: Background— Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)–mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI. Methods and Results— A total of 2571 participants in the WENBIT (Western Norway B Vitamin Intervention Trial) undergoing coronary angiography for stable angina pectoris were studied. Associations of plasma serine and glycine concentrations with risk of AMI across 2 common and functional MTHFD1 polymorphisms ( rs2236225 and rs1076991 ) were explored in Cox regression models. During a median follow-up of 4.7 years, 212 patients (8.2%) experienced an AMI. In age- and sex-adjusted analyses, plasma glycine ( P P =0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed ( P interaction =0.03 for both). Low plasma serine and glycine were associated with an increased risk of AMI among patients carrying the rs2236225 minor A allele. Similarly, low plasma glycine showed stronger risk relationship with AMI in the rs1076991 CC genotype carriers but weaker associations in patients carrying the minor T allele ( P interaction =0.02). Conclusions— Our results showed that 2 common and functional polymorphisms in the MTHFD1 gene modulate the risk associations of plasma serine and glycine with AMI. These findings emphasize the possible role of the MTHFD1 in regulating serine and glycine metabolism in relation to atherosclerotic complications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT00354081.
Published: 2016

13. A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity

Author: Jaakko T. Leinonen, Nicholas J. Timpson, Mohammad Hadi Zafarmand, Mette Hollensted, Anne E. Justice, Robert L. Hanson, Struan F.A. Grant, Frank D. Gilliland, Jesús Peralta-Romero, Diana L. Cousminer, Carol A. Wang, Jens-Christian Holm, Lindsay Fernández-Rhodes, Elina Hyppönen, Marc Vaudel, Marjo-Riitta Järvelin, Amélie Bonnefond, Esteban J. Parra, Robert I. Berkowitz, Koon K. Teo, Adnan Custovic, Christian Theil Have, Mariona Bustamante, Kari E. North, Stefan Johansson, Mustafa Atalay, Christine Frithioff-Bøjsøe, Estela Blanco, Adan Valladares-Salgado, Sylvain Sebert, Suzanne Vogelezang, Yujie Wang, Mark I. McCarthy, Timo A. Lakka, Christine Power, Raimo Joro, Oluf Pedersen, Heather M. Highland, Yik Ying Teo, Zhanghua Chen, Pål R. Njølstad, Momoko Horikoshi, William J. Gauderman, Øyvind Helgeland, Klaus Bønnelykke, Anke Hinney, Natalia Vilor-Tejedor, V. Saroja Voruganti, Niels Grarup, Sayuko Kobes, Shana E. McCormack, Christopher D. Brown, Alessandra Chesi, Nancy F. Butte, Triinu Peters, Miguel Cruz, Johan G. Eriksson, Torben Hansen, Babette S. Zemel, Terho Lehtimäki, Niina Pitkänen, Akram Alyass, Vincent W. V. Jaddoe, Elisabeth Thiering, Jonathan P. Bradfield, Eileen Tai-Hui Boh, Janine F. Felix, Olli T. Raitakari, Philippe Froguel, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Martine Vrijheid, Ville Karhunen, Mika Kähönen, Marie Standl, Angela Simpson, Seang-Mei Saw, David Meyre, Anthony G. Comuzzie, Mickaël Canouil, Tarunveer S. Ahluwalia, John A. Curtin, Barbera D. C. van Schaik, Johannes Hebebrand, Elisabeth Widen, Tanja G. M. Vrijkotte, Leslie J. Baier, Sheila Gahagan, Joachim Heinrich, Claire Monnereau, Jesús Vioque, Hans Bisgaard, Hakon Hakonarson, Estelle Lowry, Craig E. Pennell, Shelley A. Cole, Thorkild I. A. Sørensen, André G. Uitterlinden, Virpi Lindi, Genomics of Sex Differences, Institute for Molecular Medicine Finland, University of Helsinki, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Bradfield, Jonathan P., Vogelezang, Suzanne, Felix, Janine F., Chesi, Alessandra, Hyppönen, Elina, Jaddoe, Vincent W.V., Early Growth Genetics Consortium, Epidemiology and Data Science, Public and occupational health, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, APH - Global Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, ARD - Amsterdam Reproduction and Development, APH - Methodology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, obesity, Pediatric Obesity, Medizin, IDENTIFIES 3, Genome-wide association study, VARIANTS, ethnic group, single nucleotide polymorphism, genetics, bayesian analysis, genes, Association Studies Article, Child, Genetics (clinical), 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, child, 0303 health sciences, adult, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Chromosome Mapping, General Medicine, 3. Good health, Female, body mass index procedure, childhood obesity, Life Sciences & Biomedicine, asian, Biochemistry & Molecular Biology, SUSCEPTIBILITY LOCI, DATABASE, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Wilms Tumor, Childhood obesity, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, MANAGEMENT, Humans, Genetic Predisposition to Disease, genome, Molecular Biology, 030304 developmental biology, genome-wide association study, Science & Technology, Early Growth Genetics Consortium, Case-control study, Bayes Theorem, 06 Biological Sciences, medicine.disease, Obesity, MC3R GENE, Genetic Loci, Case-Control Studies, 1182 Biochemistry, cell and molecular biology, Body mass index, Genome-Wide Association Study
Abstract: Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently
Published: 2019

14. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

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

15. The genetic architecture of sporadic and recurrent miscarriage

Author: J Southcombe, David M. Hougaard, Penelope A. Lind, Ana Luiza Gonçalves Soares, Iona Y Millwood, Teresa Ferreira, Liming Li, Donald F. Conrad, Viktorija Kukushkina, Krina T. Zondervan, Jonas Bybjerg-Grauholm, Stefan Johansson, Christian M. Becker, Rasmus Nielsen, Preben Bo Mortensen, Avinash Ramu, Benjamin M. Neale, Nicholas G. Martin, Jodie N. Painter, Ingrid Granne, Ling Yang, Robin G. Walters, Reedik Mägi, Scott D. Gordon, Xin Jin, Andres Metspalu, Cecilia M. Lindgren, Christiana Kartsonaki, Pål R. Njølstad, Harold Snieder, Maarja Lepamets, Zhengming Chen, Triin Laisk, Bo Jacobsson, Andrew P. Morris, Sarah E. Medland, Øyvind Helgeland, Margaret F. Lippincott, Grant W. Montgomery, Siyang Liu, Samantha Laber, Andres Salumets, Stephanie B. Seminara, Kuang Lin, Marianne Andersen, Jonas Bacelis, Debbie A Lawlor, Chia-Yen Chen, Julius Juodakis, and Dale R. Nyholt
Subjects: Genetics, 0303 health sciences, 030219 obstetrics & reproductive medicine, Biology, medicine.disease, Genetic architecture, Miscarriage, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Recurrent miscarriage, Mendelian randomization, Genetic variation, medicine, 030304 developmental biology, Genetic association, Chromosome 13
Abstract: Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%,Pmeta=3.2×-8(CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located nearFGF9involved in pregnancy maintenance3and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%,Pmeta=1.3×-8in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.
Published: 2019
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16. Genome-wide association study reveals a dynamic role of common genetic variation in infant and early childhood growth

Author: Camilla Stoltenberg, Petur Benedikt Juliusson, Bo Jacobsson, Rolv T. Lie, Oddgeir L. Holmen, Jonas Bacelis, Pål R. Njølstad, Kristian Hveem, Marc Vaudel, Anders Molven, Jørn V. Sagen, Julius Juodakis, Per Magnus, Haakon Lindekleiv, Stefan Johansson, Gun Peggy Knudsen, and Øyvind Helgeland
Subjects: 2. Zero hunger, Genetics, 0303 health sciences, Leptin receptor, Leptin, 030305 genetics & heredity, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, 03 medical and health sciences, Genetic variation, Early childhood, Body mass index, 030304 developmental biology
Abstract: Infant and childhood growth are dynamic processes characterized by drastic changes in fat mass and body mass index (BMI) at distinct developmental stages. To elucidate how genetic variation influences these processes, we performed the first genome-wide association study (GWAS) of BMI measurements at 12 time points from birth to eight years of age (9,286 children, 74,105 measurements) in the Norwegian Mother and Child Cohort Study (MoBa) with replication in 5,235 children (41,502 measurements). We identified five loci associated with BMI at distinct developmental stages with different patterns of association. Notably, we identified a novel transient effect in the leptin receptor (LEPR) locus, with no effect at birth, increasing effect on BMI in infancy, peaking at 6-12 months (rs2767486, P6m = 2.0 × 10−21, β6m = 0.16) and little effect after age five. A similar transient effect was found near the leptin gene (LEP), peaking at 1.5 years of age (rs10487505, P1.5y = 1.3 × 10−8, β1.5y = 0.079). Both signals are protein quantitative trait loci (pQTLs) for soluble LEPR and LEP in plasma in adults and independent from signals associated with other adult traits mapped to the respective genes, suggesting novel key roles of common variation in the leptin signaling pathway for healthy infant growth. Hence, our longitudinal analysis uncovers a complex and dynamic influence of common variation on BMI during infant and early childhood growth, dominated by the LEP-LEPR axis in infancy.
Published: 2018

17. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018

18. Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

Author: Loreto Santa-Marina, Frank Geller, Julie A. Marsh, Mike Bartels, Xavier Estivill, Christine Power, Ronny Myhre, Momoko Horikoshi, Ellen A. Nohr, Andrew T. Hattersley, Jani Heikkinen, Andrew R. Wood, Debbie A Lawlor, Alana Cavadino, Dorret I. Boomsma, Berthold Hocher, Louis J. Muglia, Wei Ang, Marie-France Hivert, Jodie N. Painter, Eina Hypponen, Marcus A. Tuke, Timothy M. Frayling, Kathryn L. Lunetta, Sheila J. Barton, Luigi Bouchard, Leda Chatzi, Shikta Das, Eskil Kreiner-Møller, Sylvain Sebert, David M. Evans, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Katherine S. Ruth, Diane J. Berry, Denise M. Scholtens, Hakon Hakonarson, William L. Lowe, Christoph Reichetzeder, Samuel E. Jones, Tim D. Spector, John W. Holloway, Rachel M. Freathy, Rebecca C Richmond, Caroline L Relton, Penelope A. Lind, Mads Melbye, Susan M. Ring, Marjo-Riitta Järvelin, Catherine Allard, Anna Murray, Craig E. Pennell, Mark I. McCarthy, Albert Hofman, Grant W. Montgomery, Joanne M. Murabito, Bjarke Feenstra, Hans Bisgaard, Hanieh Yaghootkar, M. Geoffrey Hayes, Struan F.A. Grant, Vincent W. V. Jaddoe, Michael N. Weedon, Robin N Beaumont, Jonathan P. Bradfield, Gonneke Willemsen, Ville Huikari, Jessica Tyrrell, Catherine Potter, Michael Nodzenski, Hazel Inskip, Janine F. Felix, Ge Zhang, Letizia Marullo, Sarah Metrustry, Jouke-Jan Hottenga, Manolis Kogevinas, Jeffrey C. Murray, Verena Sengpiel, Sarah E. Medland, Pål R. Njølstad, Øyvind Helgeland, Bo Jacobsson, Thorkild I. A. Sørensen, and Nicole M. Warrington
Subjects: Genetics, 0303 health sciences, Fetus, Offspring, Birth weight, Single-nucleotide polymorphism, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Allele, TCF7L2, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about how maternal genetic variation influences fetal growth. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth.We meta-analysed GWAS data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects.Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9 and CYP3A7) showed evidence of association with offspring birth weight at P-8. The SEM analyses showed at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration.The identified associations indicate effects of maternal glucose, cytochrome P450 activity and gestational duration, and potential effects of maternal blood pressure and immune function on fetal growth. Further characterization of these associations, for example in mechanistic and causal analyses, will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
Published: 2015

19. Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis

Author: Ronny Myhre, Stefan Johansson, Ge Zhang, Candice Lengyel, Øyvind Helgeland, Jonas Bacelis, Louis J. Muglia, Mikko Hallman, Verena Sengpiel, Pål R. Njølstad, Kari Teramo, Bo Jacobsson, Department of Obstetrics and Gynecology, Clinicum, and HUS Gynecology and Obstetrics
Subjects: Birth weight, Denmark, Parenteral transmission, CHILDHOOD GROWTH, Mothers, Gestational Age, DETERMINANTS, Biology, Polymorphism, Single Nucleotide, 3123 Gynaecology and paediatrics, Pregnancy, Mendelian randomization, INSTRUMENTAL VARIABLES, LENGTH, medicine, Humans, Finland, Genetics, Fetus, PRETERM, Norway, COMPLEX TRAITS, Confounding, Body Weight, Infant, Newborn, Gestational age, Mendelian Randomization Analysis, ASSOCIATION, General Medicine, medicine.disease, MULTIPLE GENETIC-VARIANTS, Body Height, 3. Good health, Causality, Phenotype, Haplotypes, RISK-FACTORS, Medicine, Female, WEIGHT, Demography, Research Article
Abstract: Background Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach. Methods and Findings We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP) data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway). We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10−9), birth weight (p = 2.19 × 10−15), and gestational age (p = 1.51 × 10−7). Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424) and demonstrated a significant (p = 0.0234) causal effect of every 1 cm increase in maternal height resulting in ~0.4 more gestational d. Limitations of this study include potential influences in causal inference by biological pleiotropy, assortative mating, and the nonrandom sampling of study subjects. Conclusions Our results demonstrate that the observed association between maternal height and fetal growth measures (i.e., birth length and birth weight) is mainly defined by fetal genetics. In contrast, the association between maternal height and gestational age is more likely to be causal. In addition, our approach that utilizes the genetic score derived from the nontransmitted maternal haplotype as a genetic instrument is a novel extension to the Mendelian randomization methodology in casual inference between parental phenotype (or exposure) and outcomes in offspring., Using a Mendelian randomization approach, Ge Zhang and colleagues examine the causal relationship between maternal height, birth size, and gestational age at birth., Editors' Summary Background Soon after the birth of a baby, doting parents send messages to friends and relatives or post information on social media sites to let everyone know when their new baby boy or girl was born. They may also post information about how heavy he/she was at birth and his/her length. These pregnancy outcomes, together with gestational age at birth (the length of time that a baby has spent developing in its mother’s womb), affect the baby’s immediate health and survival. Importantly, however, these pregnancy outcomes are also associated with the risk of long-term adverse health outcomes such as obesity, cardiometabolic disorders (heart disease and conditions such as diabetes that affect how the body makes energy from food), and neuropsychiatric conditions (mental disorders attributable to diseases of the nervous system, such as depression). For example, some studies have shown an association between low birth weight and an increased risk of type 2 diabetes later in life. Why Was This Study Done? Identification of the environmental and genetic factors that causally influence gestational age, length, and weight at birth would improve our understanding of why these pregnancy outcomes are associated with disease during adulthood and could help in the design of strategies to prevent these diseases. Epidemiological studies (investigations that examine disease patterns in populations) suggest that, compared to tall mothers, short mothers tend to deliver their babies at earlier gestational ages, with lower birth weights and lengths. Epidemiological studies cannot show, however, whether variations in maternal height cause variations in pregnancy outcomes. Other characteristics shared by tall mothers might actually determine the size and gestational age of their offspring (confounding). Here, the researchers use “Mendelian randomization” to assess the causal effect of maternal height on the size and gestational age at birth of babies. Because gene variants are inherited randomly, they are not prone to confounding. So, if maternal height actually affects gestational age and size at birth, genetic variants (instruments) that affect maternal height should be associated with differences in gestational age and size at birth, provided confounding due to the transmission of parental alleles (variant forms of genes; people have two alleles of every gene, one inherited from each parent) is avoided by adjusting for the baby’s genotype. What Did the Researchers Do and Find? The researchers used phenotype data (observable characteristics such as maternal height and birth weight of the baby) and single nucleotide polymorphism (SNP; a type of genetic variant) data obtained from 3,486 Nordic mother/baby pairs. Analysis of the phenotype data indicated that maternal height was significantly associated with length, weight, and gestational age at birth (a significant association is unlikely to have arisen by chance). For their Mendelian randomization analysis, the researchers constructed a genetic score based on 697 SNPs known to be associated with adult height. To avoid confounding due to genetic sharing between the mother and baby, they determined which of the height-associated alleles each baby had inherited from its mother and used the nontransmitted haplotype score as a genetic instrument for maternal height (a haplotype is a set of DNA variations that are inherited together). Birth length and weight were significantly associated with both the maternal and paternal transmitted haplotype scores but not with the maternal nontransmitted haplotype score. However, gestational age was significantly but modestly associated with the maternal nontransmitted haplotype score. What Do These Findings Mean? The validity of the assumptions that underlie the Mendelian randomization approach and the design of the studies supplying the data for this analysis may affect the accuracy of the findings reported here. Nevertheless, these findings suggest that the observed association between maternal height and fetal growth measurements is mainly determined by the genetics of the baby. That is, differences in maternal height do not cause differences in birth weight or length. Rather, some of the gene variants that the baby inherits from its mother determine both its size and its mother’s height. These findings also provide weak evidence that the association between maternal height and gestational age is causal. Maternal height might, for example, causally influence gestational age by limiting the space available for the baby’s growth before birth. Finally, these findings introduce an extension to the Mendelian randomization approach that can be used to investigate causal associations between parental characteristics and offspring outcomes. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001865. The March of Dimes, a not-for-profit organization for pregnancy and baby health, provides information about low birth weight and its consequences Nemours, a not-for-profit organization for child health, provides information about the weight of newborn babies (in English and Spanish) Wikipedia has pages on birth weight, gestational age, and Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) MedlinePlus provides information and links to additional resources about birth weight and a brief explanation of gestational age (in English and Spanish)
Published: 2015

20. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Dragana Vuckovic, Mariaelisa Graff, M. Arfan Ikram, Marit E. Jørgensen, Lia E. Bang, Gerome Breen, Torben Jørgensen, Matthias Blüher, Ivan Brandslund, Hester M. den Ruijter, Ian Ford, Timo A. Lakka, Jennifer Wessel, J. Wouter Jukema, Adam S. Butterworth, Iris M. Heid, Xiuqing Guo, Shuai Wang, Paul L. Auer, Tamuno Alfred, Katja K.H. Aben, Inês Barroso, Gail Davies, Helen Griffiths, Heather M. Highland, Myriam Fornage, Claudia Langenberg, Daniel R. Witte, Ilaria Gandin, Kent D. Taylor, Patrick T. Ellinor, Matti Uusitupa, Laura M. Yerges-Armstrong, Fotios Drenos, Lars Wallentin, Joanna M. M. Howson, Jaakko Tuomilehto, Andrew D. Morris, Lawrence F. Bielak, Mengmeng Du, Andrew J. Lotery, Ailith Pirie, Francis S. Collins, Eva Rabing Brix Petersen, Carolina Medina-Gomez, Manuel A. Rivas, Maria Karaleftheri, Jan-Håkan Jansson, Peter Kovacs, Jaspal S. Kooner, Markku Laakso, Fredrik Karpe, Markus Perola, Anubha Mahajan, Heather M. Stringham, Rohit Varma, Alex W. Hewitt, Chris J. Packard, Andrew C. Heath, Claudia Schurmann, Nele Friedrich, David Lamparter, Vanisha Mistry, Renée de Mutsert, Unnur Thorsteinsdottir, Naveed Sattar, Jennifer E. Huffman, Dale R. Nyholt, Johanna Kuusisto, Angela L. Mazul, Hanieh Yaghootkar, George Dedoussis, Yadav Sapkota, Elizabeth K. Speliotes, Amanda J. Cox, Jane Gibson, Christian Theil Have, Penny Gordon-Larsen, Alisa K. Manning, Jaakko Kaprio, Sita H. Vermeulen, Stella Trompet, Yucheng Jia, Dennis O. Mook-Kanamori, Torben Hansen, Kathleen Stirrups, Jean Ferrières, Douglas F. Easton, Ruth J. F. Loos, Gerard Pasterkamp, John M. Starr, Tellervo Korhonen, Betina H. Thuesen, Olov Rolandsson, Veikko Salomaa, Eric B. Larson, Thomas F. Vogt, John Danesh, Honghuang Lin, Gaëlle Marenne, Timothy M. Frayling, Anette Varbo, Daniel I. Chasman, Aliki-Eleni Farmaki, Lorraine Southam, Martina Müller-Nurasyid, Katharine R. Owen, Paul Mitchell, Ching-Ti Liu, Massimiliano Cocca, Anette P. Gjesing, Charles Kooperberg, Rebecca S. Fine, Wei Gan, Amy J. Swift, Gerard Tromp, Krina T. Zondervan, Henrik Vestergaard, Katherine S. Ruth, Angela D'Eustacchio, Uwe Völker, Beverley Balkau, Hayato Tada, Ingrid B. Borecki, Xueling Sim, Gudmar Thorleifsson, Wei Zhou, Yiqin Wang, Eleftheria Zeggini, Cora E. Lewis, Michael Boehnke, Evangelos Evangelou, Gabriel Cuellar-Partida, Sven Bergmann, Tinca J. C. Polderman, Philippe Amouyel, Roberta McKean-Cowdin, Ellen W. Demerath, Marco Brumat, Kjell Nikus, Anneke I den Hollander, Stefan Gustafsson, Allan Linneberg, Peter T. Campbell, Weihua Zhang, Leslie A. Lange, Gina M. Peloso, Jonathan P. Bradfield, Cornelia M. van Duijn, Xiaowei Zhan, Marie-Pierre Dubé, Liang He, André G. Uitterlinden, Anne Tybjærg-Hansen, Yingchang Lu, Wei Zhao, Liang Sun, Yii-Der Ida Chen, Paul I. W. de Bakker, Børge G. Nordestgaard, Karina Meidtner, Carsten A. Böger, Lynne E. Wagenknecht, Eric Kim, Pang Yao, Olli T. Raitakari, Nanette R. Lee, René S. Kahn, Lili Milani, Tessel E. Galesloot, Jussi Hernesniemi, Valgerdur Steinthorsdottir, Jie Yao, Eulalia Catamo, Kerrin S. Small, Sara M. Willems, Marcelo P. Segura-Lepe, Cecilia M. Lindgren, Asif Rasheed, Gonçalo R. Abecasis, Adam E. Locke, Konstantin Strauch, Albert V. Smith, Anke R. Hammerschlag, Frida Renström, Zoltán Kutalik, Giovanni Veronesi, Paul M. Ridker, David J. Carey, Yao Hu, Jaana Lindström, John Andrew Pospisilik, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Mary F. Feitosa, John R. B. Perry, Anne E. Justice, Ele Ferrannini, Shuang Feng, Helen R. Warren, David J. Roberts, Igor Rudan, Jeffrey R. O'Connel, Alison Pattie, Christopher P. Nelson, Lars Lind, Feijie Wang, Tamara B. Harris, Keng-Hung Lin, Jerome I. Rotter, Matthew A. Allison, Robin Young, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Stefan Johansson, Alexander P. Reiner, Jing Hua Zhao, Poorva Mudgal, Tim D. Spector, Paul W. Franks, Loes M. Olde Loohuis, Harvey D. White, Pirjo Komulainen, Michelle L. O'Donoghue, Todd L. Edwards, Ozren Polasek, Andrew R. Wood, Dermot F. Reilly, Myriam Rheinberger, Cramer Christensen, G. Kees Hovingh, Hidetoshi Kitajima, Kristin L. Young, Audrey Y. Chu, Megan L. Grove, Suthesh Sivapalaratnam, Lisa Bastarache, Martin den Heijer, Oddgeir L. Holmen, Vilmundur Gudnason, Sameer E. Al-Harthi, Dewan S. Alam, Robert E. Schoen, Jin Li, Sascha Fauser, Janie Corley, Paolo Gasparini, Niels Grarup, Guillaume Lettre, Thomas N. Person, Mark I. McCarthy, Joel N. Hirschhorn, Ying Wu, Pia R. Kamstrup, Nilesh J. Samani, Panos Deloukas, Ethan M. Lange, Helena Kuivaniemi, Mika Kähönen, Michiel L. Bots, Annette Peters, Peggy L. Peissig, Wayne Huey-Herng Sheu, Steven A. Lubitz, Stefania Cappellani, Mauno Vanhala, Andrew P. Morris, Struan F.A. Grant, Mark Walker, Trevor A. Mori, Jian'an Luan, Matthias B. Schulze, Josh C. Denny, Sarah E. Medland, Sander W. van der Laan, Maggie C.Y. Ng, Eric Boerwinkle, Tibor V. Varga, Øyvind Helgeland, Anke Tönjes, Jessica van Setten, James P. Cook, Patricia B. Munroe, Heiner Boeing, Robert A. Scott, Karen L. Mohlke, Leena Moilanen, Ayush Giri, Andrew J. Slater, Andrew T. Hattersley, Mark J. Caulfield, Tõnu Esko, Mark C. H. Groot, Nancy L. Heard-Costa, Narisu Narisu, Danish Saleheen, Valérie Turcot, Lambertus A. Kiemeney, Nicholas G. D. Masca, Ruifang Li-Gao, Jean-Claude Tardif, Xu Lin, Kathleen Mullan Harris, Antonietta Robino, Alison M. Dunning, Jonathan Tyrer, Audrey E. Hendricks, Linda Broer, Patricia A. Peyser, Jessica D. Faul, Jose C. Florez, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, John C. Chambers, Jordi Corominas Galbany, Ruth Frikke-Schmidt, David S. Crosslin, Bratati Kahali, Stavroula Kanoni, Gorm B. Jensen, Nicholas J. Wareham, Paul Elliott, Tune H. Pers, James A. Perry, Tugce Karaderi, Matt J. Neville, Marianne Benn, Svati H. Shah, Mathias Gorski, Michael Stumvoll, David Ellinghaus, Amber A. Burt, Kari E. North, Jeffrey Haessler, Rajiv Chowdhury, Folkert W. Asselbergs, Marie Moitry, Aniruddh P. Patel, Pamela J. Schreiner, Frank Kee, Donald W. Bowden, Sune F. Nielsen, Oluf Pedersen, John D. Rioux, Rainer Rauramaa, Satu Männistö, Deborah J. Thompson, Cristen J. Willer, Andre Franke, Kari Kuulasmaa, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Sekar Kathiresan, Erin B. Ware, Dawn M. Waterworth, James G. Wilson, Sandosh Padmanabhan, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Digna R. Velez Edwards, Artitaya Lophatananon, Craig E. Pennell, Gail P. Jarvik, Adelheid Lempradl, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Oscar H. Franco, Yongmei Liu, I. Sadaf Farooqi, Hannu Puolijoki, Huaixing Li, Caroline Hayward, Rudolf Uher, Veronique Vitart, Murray H. Brilliant, Kari Stefansson, Alexander Teumer, Nicholette D. Palmer, Vilmantas Giedraitis, Roel A. Ophoff, Sailaja Vedantam, Emanuele Di Angelantonio, Ken S. Lo, Grant W. Montgomery, Paul L. Huang, Praveen Surendran, Terho Lehtimäki, Katherine E. Tansey, Li-An Lin, Pål R. Njølstad, Thomas W. Winkler, Ian J. Deary, Erwin P. Bottinger, Carol A. Wang, Biological Psychology, Complex Trait Genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, 2. Zero hunger, 0303 health sciences, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Published Erratum, Computational biology, Biology, medicine.disease, Obesity, Genealogy, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, ddc:570, Genetics, medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biological sciences, Body mass index, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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20 results on '"Øyvind Helgeland"'

1. A fast wavelet-based functional association analysis replicates several susceptibility loci for birth weight in a Norwegian population

2. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

3. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents

4. 399The causal effect of BMI on neurodevelopment: a within family Mendelian randomization study using MoBa

5. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

6. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

7. The genetic architecture of sporadic and multiple consecutive miscarriage

8. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

9. Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios

10. Introducing M-GCTA a Software Package to Estimate Maternal (or Paternal) Genetic Effects on Offspring Phenotypes

11. Genome-Wide Association Study Links Autoimmune Addison’s Disease to Break of Central Tolerance

12. Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial)

13. A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity

14. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

15. The genetic architecture of sporadic and recurrent miscarriage

16. Genome-wide association study reveals a dynamic role of common genetic variation in infant and early childhood growth

17. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

18. Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

19. Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis

20. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

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