Interethnic analyses of blood pressure loci in populations of East Asian and European descent

Abstract Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.Acknowledgements Marie Loh71,72 (Institute of Health Sciences, University of Oulu, P.O.Box 5000FI-90014 Oulu, Finland and Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Niek Verweij73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Weihua Zhang72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Benjamin Lehne72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Irene Mateo Leach73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Alexander Drong75 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK), James Abbott76 (Bioinformatics Support Service, Imperial College London, South Kensington, London SW7 2AZ, UK), Sian-Tsung Tan74,77 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK and National Heart and Lung Institute, Imperial College London, London W12 0NN, UK), William R. Scott72,77 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Lung Institute, Imperial College London, London W12 0NN, UK), Gianluca Campanella72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Marc Chadeau-Hyam72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Uzma Afzal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Tõnu Esko78,79,80,81 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia and Division of Endocrinology, Children’s Hospital Boston, Longwood 300, Boston, MA 02115, USA and Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA), Sarah E. Harris82,83 (Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK), Jaana Hartiala84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA), Marcus E. Kleber86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Richa Saxena87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA), Alexandre F.R. Stewart88,89 (University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ontario K1Y 4W7, Canada and Ruddy Canadian Cardiovascular Genetics Centre, Ontario K1Y 4W7, Canada), Tarunveer S. Ahluwalia90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Imke Aits91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany), Alexessander Da Silva Couto Alves92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK), Shikta Das92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK), Jemma C. Hopewell93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK), Robert W. Koivula94 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden), Leo-Pekka Lyytikäinen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Iris Postmus97,98 (Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Netherlands Consortium for Healthy Ageing, Leiden 2333 ZC, Netherlands), Olli T. Raitakari99,100 (Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20520 Turku, Finland), Robert A. Scott101 (MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK), Rossella Sorice102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Vinicius Tragante103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Michela Traglia104,105 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute for Maternal and Child Health—IRCCS ‘‘Burlo Garofolo’’—Trieste, 34137 Trieste, Italy), Jon White106 (UCL Genetics Institute, Department of Genetics, Environment and Evolution, UCL, London WC1E 6BT, UK), Inês Barroso107,108,109 (Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK), Andrew Bjonnes87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA), Rory Collins103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Gail Davies110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Graciela Delgado86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Pieter A. Doevendans103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Lude Franke111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Ron T. Gansevoort112 (Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Tanja B. Grammer86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Niels Grarup86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Jagvir Grewal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Anna-Liisa Hartikainen113,114 (Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu FI-90014, Finland and Department of Clinical Sciences/Obsterics and Gynecology, University of Oulu, Oulu FI-90014, Finland), Stanley L. Hazen115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA), Chris Hsu117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA), Lise L.N. Husemoen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Johanne M. Justesen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Meena Kumari119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK), Wolfgang Lieb91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany), David C.M. Liewald110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Evelin Mihailov78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Lili Milani78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Rebecca Mills74 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Nina Mononen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Kjell Nikus120 (Heart Centre, Department of Cardiology, Tampere University Hospital, and University of Tampere School of Medicine, FI-33521 Tampere, Finland), Teresa Nutile102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Sarah Parish93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK), Olov Rolandsson121 (Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden), Daniela Ruggiero102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Cinzia F. Sala104 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy), Harold Snieder122 (Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Thomas H.W. Spasø90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Wilko Spiering123 (Department of Vascular Medicine, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), John M. Starr83,124 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Alzheimer Scotland Dementia Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), David J. Stott125 (Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G4 0SF, UK), Daniel O. Stram117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA), Silke Szymczak126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany), W.H.Wilson Tang115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA), Stella Trompet127 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands), Väinö Turjanmaa128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Marja Vaarasmaki130 (Department of Obstetrics and Gynecology, Oulu University Hospital, PO Box 23FI-90029 Oulu, Finland), Wiek H. van Gilst73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Dirk J. van Veldhuisen73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Jorma S. Viikari131,132 (Department of Medicine, Turku University Hospital, FI-20521 Turku, Finland and Department of Medicine, University of Turku, FI-20014 Turku, Finland), Folkert W. Asselbergs103,133,134 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK), Marina Ciullo102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Andre Franke126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany), Paul W. Franks94,121,135 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden and Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden and Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA), Steve Franks136 (Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W120HS, UK), Myron D. Gross137 (School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA), Torben Hansen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Marjo-Riitta Jarvelin72,92,138,139,140 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK and Biocenter Oulu, University of Oulu, P.O. Box 5000 Aapistie 5A, FI-90014 Oulu, Finland and Unit of Primary Care, Oulu University Hospital, Kajaanintie 50 P.O.Box 20FI-90220 Oulu, Finland and Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland), Torben Jørgensen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Wouter J. Jukema127,133,141 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht 3511 EP, Netherlands), Mika Kähönen128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Mika Kivimaki119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK), Terho Lehtimäki95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Allan Linneberg118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Oluf Pedersen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Nilesh J. Samani142,143 (Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK), Daniela Toniolo104,144 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute of Molecular GeneticsCNR, 27100 Pavia, Italy), Hooman Allayee84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA), Ian J. Deary83,110 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Winfried März86,145,146 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria and Synlab Academy, Synlab Services GmbH, Gottlieb-Daimler-Straße 25, 68165 Mannheim, Germany), Andres Metspalu78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Cisca Wijmenga111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Bruce H.W. Wolffenbuttel147 (Department of Endocrinology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Paolo Vineis72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Soterios A. KyrtopoulosNational Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens 116 35, Greece), Jos C.S. Kleinjans149 (Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, 6229ER Maastricht, Netherlands), Mark I. McCarthy75,150 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK), James Scott77 (National Heart and Lung Institute, Imperial College London, London W12 0NN, UK