David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai 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In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding. © 2019, The Author(s).
Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, United Kingdom; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Kanagawa, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka, 565-0871, Japan; deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland; Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Trust, Bradford, BD96RJ, United Kingdom; Research Unit, Area Science Park, Trieste, 34149, Italy; Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Unit of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, United Kingdom; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, United Kingdom; Cardiovascular Epidemiology Unit, Department of Public health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, United Kingdom; Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands, Groningen, Groningen, 9700 RB, Netherlands; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, 27514, NC, United States; The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, 10029, NY, United States; Division of Genomic Outcomes, Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, 90502, CA, United States; Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, 02215, MA, United States; Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, United Kingdom; Department of Cardiology, Ealing Hospital, Middlesex, Middlesex, UB1 3HW, United Kingdom; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands; The Generation R Study Group, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden; Institute for Social and Economic Research, University of Essex, Colchester, CO4 3SQ, United Kingdom; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, 98101, WA, United States; Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany; Institute of Molecular Genetics, National Research Council of Italy, Pavia, 27100, Italy; Department of Biochemistry, University of Otago, Dunedin, 9054, New Zealand; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore, 117549, Singapore; Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland; Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, 19104, PA, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, United States; Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, Netherlands; Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 4059, QLD, Australia; Malaghan Institute of Medical Research, Wellington, 6242, New Zealand; Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, 39100, Italy; MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, United Kingdom; INSERM UMR_S 1166, Sorbonne Universités, Paris, 75013, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, 75013, France; QIMR Berghofer Institute of Medical Research, Brisbane, Australia; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom; Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, 8036, Austria; Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, 8036, Austria; CONACyT, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 03940, Mexico; Department of Human Genetics, University of Chicago, Chicago, 60637, IL, United States; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, Netherlands; Alzheimer Center Department of Neurology, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, 1081HV, Netherlands; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany; Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising-Weihenstephan, 85354, Germany; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, 75108, Sweden; Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Lab for Cancer Research, Frederick, MD, United States; Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom; Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, United Kingdom; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, 21201, MD, United States; Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland, School of Medicine, Baltimore, 21201, MD, United States; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, Netherlands; Institute for Cardiogenetics, University of Lübeck, Lübeck, 23562, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, 23562, Germany; University Heart Center Luebeck, Lübeck, 23562, Germany; Charité – University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Dental and Craniofacial Sciences, Department of Periodontology and Synoptic Dentistry, Berlin, Germany; Institute of Genetics and Biophysics A. Buzzati-Traverso - CNR, Naples, 80131, Italy; Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland; Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, 110020, India; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, Skåne University Hospital, Malmö, 20502, Sweden; Genomic Research on Complex diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007, Telangana, India; ePhood Scientific Unit, ePhood SRL, Bresso (Milano), 20091, Italy; Department of Health Sciences, University of Milano, Milano, 20139, Italy; Neuroalgology Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milano, 20133, Italy; Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, United States; Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892-5635, MD, United States; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, DK-2300, Denmark; Icelandic Heart Association, Kopavogur, 201, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, 101, Iceland; Department of Genetics, University of North Carolina, Chapel Hill, 27599, NC, United States; Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, United Kingdom; Cardiovascular Medicine Unit, Department of Medicine Solna, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, 171 76, Sweden; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore City, 21224, MD, United States; Department of Cardiology, Leiden University Medical Center, Leiden, 2300 RC, Netherlands; Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, 2300RC, Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, United States; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, United States; University of Groningen, University Medical Center Groningen, Department of Cardiology, Ther Netherlands, Groningen, 9713 GZ, Netherlands; Italian Institute for Genomic Medicine (IIGM) and Dept. Medical Sciences, University of Turin, Italy, Turin, 10126, Italy; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, 63110-1093, MO, United States; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, United Kingdom; Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, United Kingdom; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 2BN, United Kingdom; School of Psychological Science, University of Bristol, Bristol, BS8 1TU, United Kingdom; Department of Medicine, GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, United States; Department of Genetic Medicine, Weill Cornell Medicine Qatar, Doha, Qatar; Computer and Systems Engineering, Alexandria University, Alexandria, Egypt; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, MI, United States; Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080, Mexico; Unidad de Investigacion de Enfermades Metabolicas, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, 64710, N.L., Mexico; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, 812-8582, Japan; Immunobiology of Dendritic Cells, Institut Pasteur, Paris, 75015, France; Inserm U1223, Paris, 75015, France; Centre for Translational Research, Institut Pasteur, Paris, 75015, France; Department of Cancer Immunology, Genentech Inc, San Francisco, 94080, CA, United States; Division of Preventive Medicine, Department of Family Medicine and Public Health, UC San Diego School of Medicine, La Jolla, 92093, CA, United States; Estonian Genome Center, University of Tartu, University of Tartu, Tartu, 51010, Estonia; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore, 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore, 169857, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 119228, SG, Singapore; Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 19839-63113, Iran; Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Health Science Center at Houston, UTHealth School of Public Health, University of Texas, Houston, 77030, TX, United States; USC-Office of Population Studies Foundation, Inc., Department of Nutrition and Dietetics, Talamban, University of San Carlos, Cebu City, 6000, Cebu, Philippines; Department of Vascular Surgery, Division of Surgical Specialties, University Medical Center Utrecht, University of Utrecht, Utrecht, Utrecht, 3584 CX, Netherlands; Digital Health Center, Hasso Plattner Institute, Universität Potsdam, Potsdam, 14482, Germany; Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, United States; Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, 34137, Italy; National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, United States; Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, United Kingdom; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, SG, Singapore; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, United States; Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 19839-63113, Iran; Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States; MEMO Research, Molecular and Clinical Medicine, University of Dundee, Dundee, DD19SY, United Kingdom; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, 17475, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, 17475, Germany; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 12713, KSA, Saudi Arabia; Department of Anthropology, University of Iceland, Reykjavik, 101, Iceland; National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust and Imperial College London, London, United Kingdom; UK Dementia Research Institute (UK DRI) at Imperial College London, London, United Kingdom; Health Data Research UK - London, London, United Kingdom; Department of Pediatrics, Erasmus University Medical Center, Rotterdam, 3015CN, Netherlands; Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, 27101, NC, United States; Medical Genetics, Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, United Kingdom; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, United States; Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland; Chinese Academy of Medical Sciences, Beijing, 100730, China; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, SE5 8AF, United Kingdom; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, 90089, CA, United States; Blizard Institute, Queen Mary University of London, London, E1 2AT, United Kingdom; Laboratory of Genome Technology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, University of Utrecht, Utrecht, Utrecht, 3584 CX, Netherlands; Shanghai Institute of Hematology, State Key Laboratory Of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Division of Endocrine and Metabolism, Tri-Service General Hospital Songshan branch, Taipei, Taiwan; School of Medicine, National Defense Medical Center, Taipei, Taiwan; Unit of Public Health Promotion, National Institute for Health and Welfare, Helsinki, Finland; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan; Department of Biomedical Informatics, Harvard Medical School, Boston, 02115, MA, United States; Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, 80636, Germany; Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB2 0SR, United Kingdom; Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore, 138672, Singapore; Health Services and Systems Research, Duke-NUS Medical School, Singapore, 169857, Singapore; Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Kuopio University Hospital, Kuopio, Finland; Bristol NIHR Biomedical Research Centre, Bristol, BS8 2BN, United Kingdom; Population Health Science, Bristol Medical School, Bristol, BS8 2BY, United Kingdom; Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan, Taipei, 112, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Taichung City, 402, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Internal Medicine A, University Medicine Greifswald, Greifswald, 17475, Germany; Department of Epidemiology and Biostatistics, Peking University Health Science Centre, Peking University, Beijing, 100191, China; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore, 138648, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 117596, Singapore; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, 27709, NC, United States; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, MD, United States; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, 22908, VA, United States; Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, 20132, Italy; Helmholtz Zentrum München, Independent Research Group Clinical Epidemiology, Neuherberg, 85764, Germany; Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, 85764, Germany; Institute of Human Genetics, Technical University of Munich, Munich, 81675, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, 80802, Germany; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Kanagawa, Japan; Laboratory of Haematology, La Timone Hospital, Marseille, France; INSERM UMR_S 1263, Center for CardioVascular and Nutrition research (C2VN), Aix-Marseille University, Marseille, France; Departamento de Economía, Universidad Autónoma Metropolitana, 09340, Mexico; Medical School, The University of Western Australia, Perth, 6009, WA, Australia; The University of Texas Health Science Center at Houston, School of Public Health, Department of Epidemiology, Human Genetics and Environmental Sciences, Houston, 77030, TX, United States; Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland; Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom; Laboratory of Neurogenetics, Bethesda, 20892, MD, United States; Data Tecnica International LLC, Glen Echo, 20812, MD, United States; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, 17475, Germany; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Headington, Oxford, OX3 7LJ, United Kingdom; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom; Department of Paediatrics, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, United Kingdom; Instituto Nacional de Medicina Genómica, 14610, Mexico; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, United Kingdom; Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, 55454, MN, United States; Gen-info Ltd, Zagreb, Croatia, Zagreb, 10000, Select a Province, Croatia; International Centre for Circulatory Health, Imperial College London, London, W2 1PG, United Kingdom; Imperial Clinical Trials Unit, Imperial College London, London, London, W12 7TA, United Kingdom; Human Evolutionary Genetics Unit, Institut Pasteur, Paris, 75015, France; Centre National de la Recherche Scientifique (CNRS) UMR2000, Paris, 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, 75015, France; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, University of Helsinki, Helsinki, 00014, Finland; Hero Heart Institute and Dyanand Medical College and Hospital, Ludhiana, Punjab, India; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States; Harvard Medical School, Boston, 02115, MA, United States; Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, 3062 PA, Netherlands; Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, 3062 PA, Netherlands; IRCCS Neuromed, Pozzilli (IS), 86077, Italy; Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, 8010, Austria; Unit of Genomics of Complex Diseases, Institut de Recerca Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; San Raffaele Research Institute, Milano, Italy; Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, FI-00271, Finland; Department of Biostatistics, and Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, United States; Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Uppsala, SE-752 37, Sweden; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, Utrecht, 3485 CX, Netherlands; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan; School of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, 560078, Karnataka, India; Diabetes Unit, KEM Hospital and Research Centre, Pune, 411101, Maharashtra, India; Symbiosis Statistical Institute, Symbiosis International University, Pune, 411007, Maharashtra, India; Panjab University, Chandigarh, India; Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom; RCSI Molecular & Cellular Therapeutics (MCT), Royal College of Surgeons in Ireland, RCSI Education & Research Centre, Beaumont Hospital, Dublin 9, Ireland; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom; School of Physiotherapy and Exercise Science, Faculty of Health Sciences, Curtin University, Perth, 6102, WA, Australia; Department of Respiratory Medicine, Ghent University Hospital, Ghent, 9000, Belgium; Department of Pathology, University of Vermont, Colchester, 05446, VT, United States; Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, 04510, Mexico; Unidad De Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080, Mexico; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece; Institute of Genetic and Biomedical Research - Support Unity, National Research Council of Italy, Rome, Italy; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, FI-00014, Finland; Department of Cardiology, Hero DMC Heart Institute, Dayanand Medical College & Hospital, Ludhiana, 141001, Punjab, India; Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, 100005, China; Centre for Population Health Sciences, Usher Institute of Population Health and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, United Kingdom; Diabetes Unit, K.E.M. Hospital Research Centre, Pune, 411011, MAH, India; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, Utrecht, 3584 CX, Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, WC1E 6DD, United Kingdom; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands; Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, United Kingdom; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, 9713GZ, Netherlands; Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, 60612, IL, United States; Department of Neurological Sciences, Rush University Medical Center, Chicago, 60612, IL, United States; Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India; Pennington Biomedical Research Center, Baton Rouge, 70808, Louisiane, United States; Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, 19104, PA, United States; Quantinuum Research LLC, San Diego, 92101, CA, United States; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, 98101, WA, United States; Center for Experimental Social Science, Department of Economics, New York University, New York, 10012, NY, United States; Research Institute for Industrial Economics (IFN), Stockholm, 102 15, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore; Imperial College Healthcare NHS Trust, London, London, W12 0HS, United Kingdom; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, 60611, IL, United States; Institute of Biomedical Technologies Milano, National Research Council of Italy (CNR), Segrate (Milano), 20090, Italy; Bio4Dreams Scientific Unit, Bio4Dreams SRL, Bio4Dreams - business nursery for life sciences, Milano, 20121, Italy; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, 24105, Germany; Department of General Practice and Primary health Care, University of Helsinki, Tukholmankatu 8 B, Helsinki, 00014, Finland; National Institute for Health and Welfare, Helsinki, Finland; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Vasa Central Hospital, Vaasa, Finland; Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, 48014, MI, United States; Montreal Heart Institute, Montreal, QC, Canada; Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Cuernavaca, 01120, Mexico; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, United States; Cardiovascular Medicine Unit, Department of Medicine Solna, Centre for Molecular Medicine, Stockholm, 171 76, Sweden; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Khoo Teck Puat - National University Children’s Medical Institute, National University Health System, Singapore, Singapore; Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, 90014, Finland; Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, 84108, UT, United States; Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 650 West 168th street, PH19-311, Newyork, 10032, NY, United States; Cell Circuits Program, Broad Institute, Cambridge, 02142, MA, United States; Department of Economics, Stockholm School of Economics, Stockholm, SE-113 83, Sweden; Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, 698167, Germany; Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom; Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, University of Utrecht, Utrecht, 3584 CX, Netherlands; Helsinki Collegium for Advanced Studies, University of Helsinki, University of Helsinki, Helsinki, 00014, Finland; University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, 24105, Germany; Institute of Epidemiology and PopGen Biobank, University of Kiel, Kiel, 24105, Schleswig Holstein, Germany; Department of Statistics, University of Auckland, Auckland, New Zealand; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, 4059, QLD, Australia; Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, Netherlands; Department of Medicine, Columbia University Medical Center, New York, NY, United States; Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, The School of Medicine, University of Dundee, Dundee, DD1 9SY, United Kingdom; School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW, Australia; Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, 6009, WA, Australia; Department of kinesiology, Laval University, Quebec, G1V 0A6, QC, Canada; Institute of Nutrition and Functional Foods, Laval University, Quebec, G1V 0A6, QC, Canada; Institute of Genetic and Biomedical Research - Support Unity, National Research Council of Italy, Sassari, 07100, Italy; Department of Clinical Genetics, Amsterdam Neuroscience, VU Medical Centre, Amsterdam, 1081HV, Netherlands; Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, 98101, WA, United States; Kaiser Permanente Washington Health Research Institute, Seattle, 98101, WA, United States; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, H3T 1J4, QC, Canada; Laboratory of Experimental Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, Utrecht, 3584 CX, Netherlands; Oklahoma Center for Neuroscience, Oklahoma City, 73104, OK, United States; Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany; Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Munich Heart Alliance, Munich, 80636, Germany; Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, 10591-6607, NY, United States; Faculty of Health Studies, University of Bradford, Bradford, BD7 1DP, West Yorkshire, United Kingdom; Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, 98101, WA, United States; Duke-NUS Medical School, National University of Singapore, Singapore, Singapore, 169857, SG, Singapore; Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany; Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2PR, United Kingdom; Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, Bristol, BS8 2PR, United Kingdom; Endocrinology, Abdominal Centre, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Folkhalsan Research Center, Helsinki, Finland; Research Program of Diabetes and Endocrinology, University of Helsinki, Helsinki, Finland; Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, 1011, Switzerland; Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, 19146, PA, United States; Unit of Genomics and Biomarkers, National Institute for Health and Welfare, Helsinki, 00271, Finland; National Heart and Lung Institute, Imperial College London, London, W12 0NN, United Kingdom; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, 10029, NY, United States; Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom; Program in Medical and Population Genetics, Broad Institute, Broad Institute, Cambridge, 02142, MA, United States
