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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.
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1 Medical Genomics Center, National Center for Global Health and Medicine, Tokyo, Japan; Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
2 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
3 Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan; Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
4 Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
5 Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
6 Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
7 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
8 Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Republic of Korea
9 Department of Genetics, University of North Carolina, Chapel Hill, USA
10 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
11 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
12 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
13 CAS Key Laboratory of Nutrition, Metabolism and Food safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
14 State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
15 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan
16 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
17 Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, USA
18 Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
19 Division of Epidemiology, Vanderbilt University Medical Center, Nashville, USA
20 Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
21 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan
22 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
23 Institute of Medical Science, The University of Tokyo, Tokyo, Japan
24 Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
25 Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
26 Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan
27 Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
28 Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan
29 Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
30 Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan
31 Faculty of Collaborative Regional Innovation, Ehime University, Matsuyama, Ehime, Japan
32 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
33 Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA; Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
34 Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai, China
35 USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines; Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines
36 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
37 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore
38 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
39 Merck Sharp Dohme Corp, Kenilworth, USA
40 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
41 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA; Division of Cancer Control and Population Sciences, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, USA
42 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
43 Unit of Epidemiology, Hebrew University-Hadassah Braun School of Public Health, Jerusalem, Israel
44 Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
45 Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
46 Chinese Academy of Medical Sciences, Beijing, China; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
47 Department of Epidemiology and Biostatistics, Imperial College London, London, UK
48 National Heart and Lung Institute, Imperial College London, London, UK
49 Medical Research Council-Public Health England (MRC-PHE) Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK; Imperial College Biomedical Research Centre, Imperial College London, London, UK; UK-Dementia Research Institute at Imperial College London, London, UK; National Institute for Health Research (NIHR) Health Protection Research Unit on Health Impacts of Environmental Hazards, London, UK; Health Data Research UK-London, London, UK
50 Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
51 Institute of Health Sciences, University of Oulu, Oulu, Finland; Department of Epidemiology and Biostatistics, Imperial College London, London, UK
52 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
53 Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Ealing Hospital NHS Trust, Middlesex, UK
54 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
55 Bioinformatics Support Service, Imperial College London, South Kensington, London, UK
56 Ealing Hospital NHS Trust, Middlesex, UK; National Heart and Lung Institute, Imperial College London, London, UK
57 Department of Epidemiology and Biostatistics, Imperial College London, London, UK; National Heart and Lung Institute, Imperial College London, London, UK
58 Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Children’s Hospital Boston, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
59 Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK; Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
60 Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA, USA; Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA, USA
61 Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
62 Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
63 University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ontario, Canada; Ruddy Canadian Cardiovascular Genetics Centre, Ontario, Canada
64 Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
65 Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, Kiel, Germany
66 Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
67 Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Oxford, UK
68 Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden
69 Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
70 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands; Netherlands Consortium for Healthy Ageing, Leiden, Netherlands
71 Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
72 MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
73 Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
74 Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
75 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; Institute for Maternal and Child Health—IRCCS ‘‘Burlo Garofolo’’—Trieste, Trieste, Italy
76 UCL Genetics Institute, Department of Genetics, Environment and Evolution, UCL, London, UK
77 Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK; University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
78 Department of Psychology, University of Edinburgh, Edinburgh, UK
79 Department of Genetics, University Medical Center, University of Groningen, Groningen, Netherlands
80 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
81 Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu, Finland; Department of Clinical Sciences/Obsterics and Gynecology, University of Oulu, Oulu, Finland
82 Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH, USA; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
83 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
84 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
85 Department of Epidemiology and Public Health, UCL, London, UK
86 Estonian Genome Center, University of Tartu, Tartu, Estonia
87 Ealing Hospital NHS Trust, Middlesex, UK
88 Heart Centre, Department of Cardiology, Tampere University Hospital, and University of Tampere School of Medicine, Tampere, Finland
89 Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, Umeå, Sweden
90 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
91 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
92 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
93 Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
94 Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK
95 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
96 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
97 Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland
98 Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
99 Department of Medicine, Turku University Hospital, Turku, Finland; Department of Medicine, University of Turku, Turku, Finland
100 Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK
101 Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden; Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, Umeå, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
102 Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK
103 School of Medicine, University of Minnesota, Minneapolis, MN, USA
104 Department of Epidemiology and Biostatistics, Imperial College London, London, UK; Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Biocenter Oulu, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland
105 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands
106 Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
107 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; Institute of Molecular GeneticsCNR, Pavia, Italy
108 Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK
109 Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Services GmbH, Mannheim, Germany
110 Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
111 National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece
112 Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
113 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
114 Iwate Tohoku Medical Megabank Organization, Iwate, Japan
115 Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, Germany, Mannheim, Germany
116 Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
117 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
118 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore; NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore
119 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
120 Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan
121 Department of Genome Science, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
122 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
123 RIKEN Center for Integrative Medical Sciences, Yokohama, Japan