Directional dominance on stature and cognition in diverse human populations.

Peter K Joshi, Tonu Esko, Hannele Mattsson, Niina Eklund, Ilaria Gandin, Teresa Nutile, Anne U Jackson, Claudia Schurmann, Albert V Smith, Weihua Zhang, Yukinori Okada, Alena Stančáková, Jessica D Faul, Wei Zhao, Traci M Bartz, Maria Pina Concas, Nora Franceschini, Stefan Enroth, Veronique Vitart, Stella Trompet, Xiuqing Guo, Daniel I Chasman, Jeffery R O'Connel, Tanguy Corre, Suraj S Nongmaithem, Yuning Chen, Massimo Mangino, Daniela Ruggiero, Michela Traglia, Aliki-Eleni Farmaki, Tim Kacprowski, Andrew Bjonnes, Ashley van der Spek, Ying Wu, Anil K Giri, Lisa R Yanek, Lihua Wang, Edith Hofer, Cornelius A Rietveld, Olga McLeod, Marilyn C Cornelis, Cristian Pattaro, Niek Verweij, Clemens Baumbach, Abdel Abdellaoui, Helen R Warren, Dragana Vuckovic, Hao Mei, Claude Bouchard, John R B Perry, Stefania Cappellani, Saira S Mirza, Miles C Benton, Ulrich Broeckel, Sarah E Medland, Penelope A Lind, Giovanni Malerba, Alexander Drong, Loic Yengo, Lawrence F Bielak, Degui Zhi, Peter J van der Most, Daniel Shriner, Reedik Mägi, Gibran Hemani, Tugce Karaderi, Zhaoming Wang, Tian Liu, Ilja Demuth, Jing Hua Zhao, Weihua Meng, Lazaros Lataniotis, Sander W van der Laan, Jonathan P Bradfield, Andrew R Wood, Amelie Bonnefond, Tarunveer S Ahluwalia, Leanne M Hall, Erika Salvi, Seyhan Yazar, Lisbeth Carstensen, Hugoline G de Haan, Mark Abney, Uzma Afzal, Matthew A Allison, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, R Graham Barr, Sebastian E Baumeister, Daniel J Benjamin, Sven Bergmann, Eric Boerwinkle, Erwin P Bottinger, Archie Campbell, Aravinda Chakravarti, Yingleong Chan, Stephen J Chanock, Constance Chen, Y-D Ida Chen, Francis S Collins, John Connell, Adolfo Correa, L Adrienne Cupples, George Davey Smith, Gail Davies, Marcus Dörr, Georg Ehret, Stephen B Ellis, Bjarke Feenstra, Mary F Feitosa, Ian Ford, Caroline S Fox, Timothy M Frayling, Nele Friedrich, Frank Geller, Generation Scotland, Irina Gillham-Nasenya, Omri Gottesman, Misa Graff, Francine Grodstein, Charles Gu, Chris Haley, Christopher J Hammond, Sarah E Harris, Tamara B Harris, Nicholas D Hastie, Nancy L Heard-Costa, Kauko Heikkilä, Lynne J Hocking, Georg Homuth, Jouke-Jan Hottenga, Jinyan Huang, Jennifer E Huffman, Pirro G Hysi, M Arfan Ikram, Erik Ingelsson, Anni Joensuu, Åsa Johansson, Pekka Jousilahti, J Wouter Jukema, Mika Kähönen, Yoichiro Kamatani, Stavroula Kanoni, Shona M Kerr, Nazir M Khan, Philipp Koellinger, Heikki A Koistinen, Manraj K Kooner, Michiaki Kubo, Johanna Kuusisto, Jari Lahti, Lenore J Launer, Rodney A Lea, Benjamin Lehne, Terho Lehtimäki, David C M Liewald, Lars Lind, Marie Loh, Marja-Liisa Lokki, Stephanie J London, Stephanie J Loomis, Anu Loukola, Yingchang Lu, Thomas Lumley, Annamari Lundqvist, Satu Männistö, Pedro Marques-Vidal, Corrado Masciullo, Angela Matchan, Rasika A Mathias, Koichi Matsuda, James B Meigs, Christa Meisinger, Thomas Meitinger, Cristina Menni, Frank D Mentch, Evelin Mihailov, Lili Milani, May E Montasser, Grant W Montgomery, Alanna Morrison, Richard H Myers, Rajiv Nadukuru, Pau Navarro, Mari Nelis, Markku S Nieminen, Ilja M Nolte, George T O'Connor, Adesola Ogunniyi, Sandosh Padmanabhan, Walter R Palmas, James S Pankow, Inga Patarcic, Francesca Pavani, Patricia A Peyser, Kirsi Pietilainen, Neil Poulter, Inga Prokopenko, Sarju Ralhan, Paul Redmond, Stephen S Rich, Harri Rissanen, Antonietta Robino, Lynda M Rose, Richard Rose, Cinzia Sala, Babatunde Salako, Veikko Salomaa, Antti-Pekka Sarin, Richa Saxena, Helena Schmidt, Laura J Scott, William R Scott, Bengt Sennblad, Sudha Seshadri, Peter Sever, Smeeta Shrestha, Blair H Smith, Jennifer A Smith, Nicole Soranzo, Nona Sotoodehnia, Lorraine Southam, Alice V Stanton, Maria G Stathopoulou, Konstantin Strauch, Rona J Strawbridge, Matthew J Suderman, Nikhil Tandon, Sian-Tsun Tang, Kent D Taylor, Bamidele O Tayo, Anna Maria Töglhofer, Maciej Tomaszewski, Natalia Tšernikova, Jaakko Tuomilehto, Andre G Uitterlinden, Dhananjay Vaidya, Astrid van Hylckama Vlieg, Jessica van Setten, Tuula Vasankari, Sailaja Vedantam, Efthymia Vlachopoulou, Diego Vozzi, Eero Vuoksimaa, Melanie Waldenberger, Erin B Ware, William Wentworth-Shields, John B Whitfield, Sarah Wild, Gonneke Willemsen, Chittaranjan S Yajnik, Jie Yao, Gianluigi Zaza, Xiaofeng Zhu, The BioBank Japan Project, Rany M Salem, Mads Melbye, Hans Bisgaard, Nilesh J Samani, Daniele Cusi, David A Mackey, Richard S Cooper, Philippe Froguel, Gerard Pasterkamp, Struan F A Grant, Hakon Hakonarson, Luigi Ferrucci, Robert A Scott, Andrew D Morris, Colin N A Palmer, George Dedoussis, Panos Deloukas, Lars Bertram, Ulman Lindenberger, Sonja I Berndt, Cecilia M Lindgren, Nicholas J Timpson, Anke Tönjes, Patricia B Munroe, Thorkild I A Sørensen, Charles N Rotimi, Donna K Arnett, Albertine J Oldehinkel, Sharon L R Kardia, Beverley Balkau, Giovanni Gambaro, Andrew P Morris, Johan G Eriksson, Margie J Wright, Nicholas G Martin, Steven C Hunt, John M Starr, Ian J Deary, Lyn R Griffiths, Henning Tiemeier, Nicola Pirastu, Jaakko Kaprio, Nicholas J Wareham, Louis Pérusse, James G Wilson, Giorgia Girotto, Mark J Caulfield, Olli Raitakari, Dorret I Boomsma, Christian Gieger, Pim van der Harst, Andrew A Hicks, Peter Kraft, Juha Sinisalo, Paul Knekt, Magnus Johannesson, Patrik K E Magnusson, Anders Hamsten, Reinhold Schmidt, Ingrid B Borecki, Erkki Vartiainen, Diane M Becker, Dwaipayan Bharadwaj, Karen L Mohlke, Michael Boehnke, Cornelia M van Duijn, Dharambir K Sanghera, Alexander Teumer, Eleftheria Zeggini, Andres Metspalu, Paolo Gasparini, Sheila Ulivi, Carole Ober, Daniela Toniolo, Igor Rudan, David J Porteous, Marina Ciullo, Tim D Spector, Caroline Hayward, Josée Dupuis, Ruth J F Loos, Alan F Wright, Giriraj R Chandak, Peter Vollenweider, Alan Shuldiner, Paul M Ridker, Jerome I Rotter, Naveed Sattar, Ulf Gyllensten, Kari E North, Mario Pirastu, Bruce M Psaty, David R Weir, Markku Laakso, Vilmundur Gudnason, Atsushi Takahashi, John C Chambers, Jaspal S Kooner, David P Strachan, Harry Campbell, Joel N Hirschhorn, Markus Perola, Ozren Polašek, James F Wilson

Journal: Nature 2015;523(7561):459-462

PMID: 26131930

Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Address: Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141, MA, USA.; Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, 02242, MA, USA.; Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, 02115, MA, USA.; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland.; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. 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Levy Place, New York, 10029, USA.; Icelandic Heart Association, Holtasmari 1, 201, Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, W2 1PG, UK.; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3HW, UK.; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8510, Japan.; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.; Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland.; Institute for Social Research, University of Michigan, 426 Thompson Street, 48104, Ann Arbor, MI, USA.; Department of Epidemiology, University of Michigan, 1415 Washington Heights, 48109, Ann Arbor, MI, USA.; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.; Institute of Population Genetics, National Research Council, Trav. 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Box 21, Helsinki, FI-00014, Finland.; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, RTP, NC, USA.; Ophthalmology, Massachusetts Eye and Ear, 243 Charles St, Boston, 02114, USA.; Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, 1142, New Zealand.; Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland.; Department of Internal Medicine, University Hospital, Route du Bugnon 44, Lausanne, 1011, Switzerland.; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA.; Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21224, USA.; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.; Division of General Internal Medicine, Massachusetts General Hospital , 50 Staniford St, Boston, 02114, MA, USA.; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764 Germany.; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, München, 81675, Germany.; Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006, Australia.; Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, 2118, MA, USA.; HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FI-00029, Finland.; National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, 01702, MA, USA.; Pulmonary Center and Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, 02118, MA, USA.; Department of Medicine, University of Ibadan, Ibadan, Nigeria.; ICAMS, University of Glasgow, 126 University Way, Glasgow, G12 8TA, UK.; Division of Epidemiology and Community Health , University of Minnesota , 1300 S 2nd Street, Minneapolis, 55454, USA.; Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland.; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland.; Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, FI-00014, Helsinki, Finland.; International Centre for Circulatory Health, Imperial College London, London, W2 1LA, UK.; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, SW7 2AZ, UK.; Department of Cardiology and Cardio thoracic Surgery Hero DMC Heart Institute, Civil Lines, 141001, Ludhiana, India.; Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.; Department Public Health Sciences, University of Virginia School of Medicine, 3232 West Complex, Charlottesville, 22908, USA.; Department of Psychological & Brain Sciences, Indiana University Bloomington, 1101 E. 10th St., Bloomington, IN 47405, USA.; Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, A-8010, Austria.; Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden.; Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.; University of Dundee, Kirsty Semple Way, Dundee, DD2 4DB, UK.; Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.; UMR INSERM U1122; IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire", INSERM, University of Lorraine, 30 Rue Lionnois, Nancy, 54000, France.; Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.; Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, 110029, India.; National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W12 0NN, UK.; Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, USA.; Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.; NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.; Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, 51010 Estonia.; Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland.; Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria.; Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia.; Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.; Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205, USA.; Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, FI-00250, Finland.; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany.; Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006, Australia.; Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, 411011, India.; Institute for Translational Genomics and Population Sciences , Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, 90502, USA.; Renal Unit, Department of Medicine, Piazzale A. Stefani 1, Verona, 37124, Italy.; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA.; Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark.; Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, 94305, CA, USA.; Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; The Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.; CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000, Lille, France.; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, SW7 2AZ, UK.; Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.; Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.; Translational Gerontology Branch, National institute on Aging, Baltimore, 21225, Maryland, USA.; Jacqui Wood Cancer Centre, Medical Research Insitute, University of Dundee, Ninewells hospital and School of Medicine, Dundee, DD1 9SY, Scotland.; Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells hospital and School of Medicine, Dundee, DD1 9SY, Scotland.; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.; Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195, Germany.; Faculty of Medicine, Imperial College London, Charing Cross Campus - St Dunstan's Road, London, W6 8RP, UK.; Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin, 14195, Germany.; Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, 02242, MA, USA.; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; Department of Medicine, University of Leipzig, Leipzig, Germany.; Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark.; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital , The Capital Region, Copenhagen, 2000, Denmark.; Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, 35294, AL, USA.; Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. box 30.001, Groningen, 9700 RB, The Netherlands.; Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, Villejuif, 94807, France.; Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, Roma, 00168, Italy.; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool, L69 3GA, UK.; Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland.; Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, University of Helsinki, Helsinki, FI-00014, Finland.; Vasa Central Hospital, Sandviksgatan 2-4, Vasa, 65130, Finland.; Folkhälsan Reasearch Centre, PB 63, University of Helsinki, Helsinki, FI-00014, Finland.; Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, FI-00290, Finland.; Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, 4006 Australia.; Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Room 1160, Salt Lake City, 84117, Utah, USA.; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.; Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.; Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.; Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.; Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, Trieste, 34149, Italy.; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, Trieste, 34137, Italy.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland.; Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland.; National Institute for Health and Welfare (THL), P.O.Box 30, Mannerheimintie 166, Helsinki, FI-00271, Finland.; Department of kinesiology, Laval University, 2300 rue de la Terrasse, Quebec, G1V 0A6, Canada.; Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, 39216, MS, USA.; Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, 20521, Finland.; Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, 20521, Finland.; University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700RB, The Netherlands.; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands.; University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, 9700RB, The Netherlands.; Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, SE-113 83, Sweden.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-171 77, Sweden.; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria.; Department of Genetics and Biostatistics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, 63108, MO, USA.; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA.; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA.; Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, 73104, OK , USA.; Department of Pharmaceutical Sciences , University of Oklahoma Health Sceienecs Center, Oklahoma City , 73104, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029, USA.; Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India.; Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.; Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, 21201, USA.; Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, 21201, USA.; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, 21201, USA.; BHF centre, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, Scotland.; Epidemiology, University of North Carolina, 137 E Franklin St., Suite 306, USA.; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin St., Suite 306, Chapel Hill, USA.; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.; Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1360, Seattle, 98101, WA, USA.; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, W2 1PG, UK.; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3HW, UK.; Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London, W2 1NY, UK.; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3HW, UK.; National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W12 0NN, UK.; Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London, W2 1NY, UK.; Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland.; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.; Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU, Edinburgh, UK.
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