. 2015 Nov;47(11):1282-1293.

doi: 10.1038/ng.3405. Epub 2015 Sep 21.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Norihiro Kato^#¹, Marie Loh^#^{2

3

4}, Fumihiko Takeuchi^#¹, Niek Verweij^#⁵, Xu Wang^#⁶, Weihua Zhang^#^{3

7}, Tanika N Kelly^#⁸, Danish Saleheen^#^{9

10

11}, Benjamin Lehne^#³, Irene Mateo Leach^#⁵, Alexander W Drong¹², James Abbott¹³, Simone Wahl^{14

14

15}, Sian-Tsung Tan^{7

16}, William R Scott^{3

16}, Gianluca Campanella³, Marc Chadeau-Hyam³, Uzma Afzal^{3

7}, Tarunveer S Ahluwalia^{17

18

19}, Marc Jan Bonder²⁰, Peng Chen⁶, Abbas Dehghan²¹, Todd L Edwards²², Tõnu Esko^{23

24

25

26}, Min Jin Go²⁷, Sarah E Harris^{28

29}, Jaana Hartiala^{30

31}, Silva Kasela²³, Anuradhani Kasturiratne³², Chiea-Chuen Khor^{6

33

34

35}, Marcus E Kleber³⁶, Huaixing Li³⁷, Zuan Yu Mok³⁸, Masahiro Nakatochi³⁹, Nur Sabrina Sapari³⁸, Richa Saxena⁴⁰, Alexandre F R Stewart^{41

42}, Lisette Stolk⁴³, Yasuharu Tabara⁴⁴, Ai Ling Teh⁴⁵, Ying Wu⁴⁶, Jer-Yuarn Wu^{47

48}, Yi Zhang^{49

50}, Imke Aits⁵¹, Alexessander Da Silva Couto Alves⁵², Shikta Das⁵², Rajkumar Dorajoo³³, Jemma C Hopewell⁵³, Yun Kyoung Kim²⁷, Robert W Koivula⁵⁴, Jian'an Luan⁵⁵, Leo-Pekka Lyytikäinen^{56

57}, Quang N Nguyen⁵⁸, Mark A Pereira⁵⁹, Iris Postmus^{60

61}, Olli T Raitakari^{62

63}, Molly Scannell Bryan^#⁶⁴, Robert A Scott⁵⁵, Rossella Sorice⁶⁵, Vinicius Tragante⁶⁶, Michela Traglia^{67

68}, Jon White⁶⁹, Ken Yamamoto⁷⁰, Yonghong Zhang⁷¹, Linda S Adair⁷², Alauddin Ahmed⁷³, Koichi Akiyama¹, Rasheed Asif⁹, Tin Aung⁷⁴, Inês Barroso^{75

76

77}, Andrew Bjonnes⁴⁰, Timothy R Braun⁷⁸, Hui Cai^{79

80}, Li-Ching Chang⁴⁷, Chien-Hsiun Chen^{47

48}, Ching-Yu Cheng^{6

34

74

81}, Yap-Seng Chong^{45

82}, Rory Collins⁵³, Regina Courtney^{79

80}, Gail Davies^{29

83}, Graciela Delgado³⁶, Loi D Do⁵⁸, Pieter A Doevendans⁶⁶, Ron T Gansevoort⁸⁴, Yu-Tang Gao⁸⁵, Tanja B Grammer³⁶, Niels Grarup¹⁷, Jagvir Grewal^{3

7}, Dongfeng Gu⁸⁶, Gurpreet S Wander⁸⁷, Anna-Liisa Hartikainen^{88

89

90}, Stanley L Hazen^{91

92}, Jing He⁹³, Chew-Kiat Heng⁹⁴, James E Hixson⁹⁵, Albert Hofman²¹, Chris Hsu⁹⁶, Wei Huang⁹⁷, Lise L N Husemoen⁹⁸, Joo-Yeon Hwang²⁷, Sahoko Ichihara⁹⁹, Michiya Igase¹⁰⁰, Masato Isono¹, Johanne M Justesen¹⁷, Tomohiro Katsuya^{101

102}, Muhammad G Kibriya⁶⁴, Young Jin Kim²⁷, Miyako Kishimoto¹⁰³, Woon-Puay Koh^{6

104}, Katsuhiko Kohara¹⁰⁰, Meena Kumari¹⁰⁵, Kenneth Kwek¹⁰⁶, Nanette R Lee^{107

108}, Jeannette Lee⁶, Jiemin Liao^{34

74}, Wolfgang Lieb⁵¹, David C M Liewald^{29

83}, Tatsuaki Matsubara¹⁰⁹, Yumi Matsushita¹⁰³, Thomas Meitinger^{110

111}, Evelin Mihailov²³, Lili Milani²³, Rebecca Mills⁷, Nina Mononen^{56

57}, Martina Müller-Nurasyid^{112

113

114}, Toru Nabika¹¹⁵, Eitaro Nakashima^{116

117}, Hong Kiat Ng³⁸, Kjell Nikus¹¹⁸, Teresa Nutile⁶⁵, Takayoshi Ohkubo¹¹⁹, Keizo Ohnaka¹²⁰, Sarah Parish⁵³, Lavinia Paternoster¹²¹, Hao Peng⁷¹, Annette Peters^{122

114}, Son T Pham⁵⁸, Mohitha J Pinidiyapathirage³², Mahfuzar Rahman^{73

123}, Hiromi Rakugi¹⁰², Olov Rolandsson¹²⁴, Michelle Ann Rozario³⁸, Daniela Ruggiero⁶⁵, Cinzia F Sala⁶⁷, Ralhan Sarju⁸⁷, Kazuro Shimokawa¹, Harold Snieder¹²⁵, Thomas Sparsø¹⁷, Wilko Spiering¹²⁶, John M Starr^{29

127}, David J Stott¹²⁸, Daniel O Stram⁹⁶, Takao Sugiyama¹²⁹, Silke Szymczak¹³⁰, W H Wilson Tang^{91

131}, Lin Tong⁶⁴, Stella Trompet¹³², Väinö Turjanmaa^{133

134}, Hirotsugu Ueshima^{135

136}, André G Uitterlinden^{21

43}, Satoshi Umemura¹³⁷, Marja Vaarasmaki^{88

89

90}, Rob M van Dam⁶, Wiek H van Gilst⁵, Dirk J van Veldhuisen⁵, Jorma S Viikari^{138

139}, Melanie Waldenberger^{14

122}, Yiqin Wang³⁷, Aili Wang⁷¹, Rory Wilson^{14

122}, Tien-Yin Wong^{34

74}, Yong-Bing Xiang⁸⁵, Shuhei Yamaguchi¹⁴⁰, Xingwang Ye³⁷, Robin D Young¹⁰, Terri L Young^{141

142}, Jian-Min Yuan¹⁴³, Xueya Zhou^{144

145

146}, Folkert W Asselbergs^{66

147

148}, Marina Ciullo⁶⁵, Robert Clarke⁵³, Panos Deloukas^{149

150}, Andre Franke¹³⁰, Paul W Franks^{54

124

151}, Steve Franks¹⁵², Yechiel Friedlander¹⁵³, Myron D Gross¹⁵⁴, Zhirong Guo⁷¹, Torben Hansen¹⁷, Marjo-Riitta Jarvelin^{2

52

90

155

156}, Torben Jørgensen⁹⁸, J Wouter Jukema^{132

147

157}, Mika Kähönen^{133

134}, Hiroshi Kajio¹⁰³, Mika Kivimaki¹⁰⁵, Jong-Young Lee^{158

159}, Terho Lehtimäki^{56

57}, Allan Linneberg^{98

160

161}, Tetsuro Miki¹⁰⁰, Oluf Pedersen¹⁷, Nilesh J Samani^{162

163}, Thorkild I A Sørensen^{17

121

164}, Ryoichi Takayanagi¹⁶⁵, Daniela Toniolo^{67

166}; BIOS-consortium; CARDIo GRAMplusCD; LifeLines Cohort Study; InterAct Consortium; Habibul Ahsan⁶⁴, Hooman Allayee^{30

31}, Yuan-Tsong Chen⁴⁷, John Danesh^{10

167}, Ian J Deary^{29

83}, Oscar H Franco²¹, Lude Franke²⁰, Bastiaan T Heijman¹⁶⁸, Joanna D Holbrook⁴⁵, Aaron Isaacs²¹, Bong-Jo Kim²⁷, Xu Lin³⁷, Jianjun Liu^{6

33}, Winfried März^{36

169

170}, Andres Metspalu²³, Karen L Mohlke⁴⁶, Dharambir K Sanghera⁷⁸, Xiao-Ou Shu^{79

80}, Joyce B J van Meurs⁴³, Eranga Vithana^{34

74

141}, Ananda R Wickremasinghe³², Cisca Wijmenga²⁰, Bruce H W Wolffenbuttel¹⁷¹, Mitsuhiro Yokota¹⁷², Wei Zheng^{79

80}, Dingliang Zhu^{49

50}, Paolo Vineis³, Soterios A Kyrtopoulos¹⁷³, Jos C S Kleinjans¹⁷⁴, Mark I McCarthy^{12

175}, Richie Soong^{38

176}, Christian Gieger^{14

122}, James Scott¹⁶, Yik-Ying Teo^#^{6

33

74

177

178

179}, Jiang He^#⁸, Paul Elliott^#³, E Shyong Tai^#^{6

101

180}, Pim van der Harst^#^{5

20

147}, Jaspal S Kooner^#^{7

16

181}, John C Chambers^#^{3

7

181}

Affiliations

¹ Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
² Institute of Health Sciences, University of Oulu, Oulu, Finland.
³ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁴ Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (ASTAR), Singapore.
⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁶ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
⁷ Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.
⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
⁹ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹⁰ Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
¹¹ Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹³ Bioinformatics Support Service, Imperial College London, London, UK.
¹⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁵ German Center for Diabetes Research (DZD), Neuherberg, Germany.
¹⁶ National Heart and Lung Institute, Imperial College London, London, UK.
¹⁷ Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Steno Diabetes Center, Gentofte, Denmark.
²⁰ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²¹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
²² Vanderbilt Epidemiology Center, Center for Human Genetics Research, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
²³ Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁴ Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA.
²⁵ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
²⁶ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
²⁷ Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.
²⁸ Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and Medical Research Council (MRC) Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
²⁹ Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁰ Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
³¹ Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
³² Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
³³ Genome Institute of Singapore, ASTAR, Singapore.
³⁴ Department of Ophthalmology, National University of Singapore, Singapore.
³⁵ Department of Paediatrics, National University of Singapore, Singapore.
³⁶ Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
³⁷ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
³⁸ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
³⁹ Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
⁴⁰ Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ottawa, Ontario, Canada.
⁴² Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada.
⁴³ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁴ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁵ Singapore Institute for Clinical Sciences (SICS), ASTAR, Singapore.
⁴⁶ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁷ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴⁸ School of Chinese Medicine, China Medical University, Taichung, Taiwan.
⁴⁹ State Key Laboratory of Medical Genetics, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵⁰ Shanghai Institute of Hypertension, Shanghai, China.
⁵¹ Institute of Epidemiology and Biobank popgen, Christian Albrechts University of Kiel, Kiel, Germany.
⁵² Department of Epidemiology and Biostatistics, MRC Health Protection Agency (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁵³ Clinical Trials Support Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵⁴ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
⁵⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁵⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
⁵⁷ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
⁵⁸ Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam.
⁵⁹ School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁶⁰ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁶¹ Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.
⁶² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁶³ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁶⁴ Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
⁶⁵ Institute of Genetics and Biophysics A Buzzati-Traverso, CNR, Naples, Italy.
⁶⁶ Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁶⁷ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
⁶⁸ Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo', Trieste, Italy.
⁶⁹ University College London Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.
⁷⁰ Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁷¹ Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China.
⁷² Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
⁷³ UChicago Research Bangladesh, Uttara, Dhaka, Bangladesh.
⁷⁴ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁷⁵ Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, UK.
⁷⁶ National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷⁷ University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷⁸ Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁷⁹ Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
⁸⁰ Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
⁸¹ Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore.
⁸² Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁸³ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁸⁴ Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁸⁵ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
⁸⁶ Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁸⁷ Dayanand Medical College and Hospital Unit, Hero DMC Heart Institute, Ludhiana, India.
⁸⁸ Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.
⁸⁹ Medical Research Center, University of Oulu, Oulu, Finland.
⁹⁰ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁹¹ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁹² Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁹³ Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
⁹⁴ Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore.
⁹⁵ Human Genetics Center, University of Texas School of Public Health at Houston, Houston, Texas, USA.
⁹⁶ University of Southern California Keck School of Medicine, Los Angeles, California, USA.
⁹⁷ Department of Genetics, Chinese National Human Genomic Center, Shanghai, China.
⁹⁸ Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
⁹⁹ Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.
¹⁰⁰ Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
¹⁰¹ Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁰² Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁰³ National Center for Global Health and Medicine, Toyama, Japan.
¹⁰⁴ Duke-National University of Singapore Graduate Medical School, Singapore.
¹⁰⁵ Department of Epidemiology and Public Health, University College London, London, UK.
¹⁰⁶ K.K. Women's and Children's Hospital, Singapore.
¹⁰⁷ University of San Carlos Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.
¹⁰⁸ Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines.
¹⁰⁹ Department of Internal Medicine, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
¹¹⁰ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹¹ Institute of Human Genetics, Technische Universität München, Munich, Germany.
¹¹² Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹³ Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany.
¹¹⁴ German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
¹¹⁵ Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan.
¹¹⁶ Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹¹⁷ Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.
¹¹⁸ Heart Centre, Department of Cardiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
¹¹⁹ Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.
¹²⁰ Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹²¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹²² Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹²³ Research and Evaluation Division, Bangladesh Rehabilitation Assistance Committee (BRAC), Dhaka, Bangladesh.
¹²⁴ Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå Universitet, Umeå, Sweden.
¹²⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁶ Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²⁷ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
¹²⁸ Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
¹²⁹ Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
¹³⁰ Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
¹³¹ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹³² Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
¹³³ Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
¹³⁴ Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
¹³⁵ Department of Health Science, Shiga University of Medical Science, Otsu, Japan.
¹³⁶ Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
¹³⁷ Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹³⁸ Division of Medicine, Turku University Hospital, Turku, Finland.
¹³⁹ Department of Medicine, University of Turku, Turku, Finland.
¹⁴⁰ Third Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan.
¹⁴¹ Neuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore Graduate Medical School, Singapore.
¹⁴² Duke Eye Center, Duke University Medical Center, Durham, North Carolina, USA.
¹⁴³ Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
¹⁴⁴ Bioinformatics Division, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.
¹⁴⁵ Center for Synthetic and Systems Biology, TNLIST, Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.
¹⁴⁶ Department of Psychiatry, University of Hong Kong, Hong Kong.
¹⁴⁷ Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)-Netherlands Heart Institute, Utrecht, the Netherlands.
¹⁴⁸ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁴⁹ William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁵⁰ King Abdulaziz University, Jeddah, Saudi Arabia.
¹⁵¹ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
¹⁵² Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK.
¹⁵³ Hebrew University, School of Public Health, Jerusalem, Israel.
¹⁵⁴ School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁵⁵ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁵⁶ Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵⁷ ICIN, Utrecht, the Netherlands.
¹⁵⁸ Ministry of Health and Welfare, Seoul, Republic of Korea.
¹⁵⁹ THERAGEN ETEX Bio Institute, Suwon, Republic of Korea.
¹⁶⁰ Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
¹⁶¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁶² Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
¹⁶³ NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
¹⁶⁴ Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
¹⁶⁵ Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan.
¹⁶⁶ Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy.
¹⁶⁷ Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁶⁸ Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹⁷⁰ Synlab Academy, Synlab Services, Mannheim, Germany.
¹⁷¹ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷² Department of Genome Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
¹⁷³ National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
¹⁷⁴ Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
¹⁷⁵ Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
¹⁷⁶ Department of Pathology, National University of Singapore, Singapore.
¹⁷⁷ National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
¹⁷⁸ Life Sciences Institute, National University of Singapore, Singapore.
¹⁷⁹ Department of Statistics and Applied Probability, National University of Singapore, Singapore.
¹⁸⁰ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹⁸¹ Imperial College Healthcare NHS Trust, London, UK.

^# Contributed equally.

PMID: 26390057
PMCID: PMC4719169
DOI: 10.1038/ng.3405

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Norihiro Kato et al. Nat Genet. 2015 Nov.

. 2015 Nov;47(11):1282-1293.

doi: 10.1038/ng.3405. Epub 2015 Sep 21.

Authors

Affiliations

¹ Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
² Institute of Health Sciences, University of Oulu, Oulu, Finland.
³ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁴ Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (ASTAR), Singapore.
⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁶ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
⁷ Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.
⁸ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
⁹ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹⁰ Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
¹¹ Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹³ Bioinformatics Support Service, Imperial College London, London, UK.
¹⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁵ German Center for Diabetes Research (DZD), Neuherberg, Germany.
¹⁶ National Heart and Lung Institute, Imperial College London, London, UK.
¹⁷ Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁸ Copenhagen Prospective Studies on Asthma in Childhood (COSPAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Steno Diabetes Center, Gentofte, Denmark.
²⁰ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²¹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
²² Vanderbilt Epidemiology Center, Center for Human Genetics Research, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
²³ Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁴ Division of Endocrinology, Children's Hospital Boston, Boston, Massachusetts, USA.
²⁵ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
²⁶ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
²⁷ Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Republic of Korea.
²⁸ Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and Medical Research Council (MRC) Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
²⁹ Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁰ Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
³¹ Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
³² Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
³³ Genome Institute of Singapore, ASTAR, Singapore.
³⁴ Department of Ophthalmology, National University of Singapore, Singapore.
³⁵ Department of Paediatrics, National University of Singapore, Singapore.
³⁶ Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
³⁷ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
³⁸ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
³⁹ Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
⁴⁰ Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴¹ University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ottawa, Ontario, Canada.
⁴² Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada.
⁴³ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁴ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁵ Singapore Institute for Clinical Sciences (SICS), ASTAR, Singapore.
⁴⁶ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁷ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴⁸ School of Chinese Medicine, China Medical University, Taichung, Taiwan.
⁴⁹ State Key Laboratory of Medical Genetics, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵⁰ Shanghai Institute of Hypertension, Shanghai, China.
⁵¹ Institute of Epidemiology and Biobank popgen, Christian Albrechts University of Kiel, Kiel, Germany.
⁵² Department of Epidemiology and Biostatistics, MRC Health Protection Agency (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁵³ Clinical Trials Support Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵⁴ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
⁵⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁵⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
⁵⁷ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
⁵⁸ Vietnam National Heart Institute, Bach Mai Hospital, Hanoi, Vietnam.
⁵⁹ School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁶⁰ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁶¹ Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.
⁶² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁶³ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁶⁴ Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
⁶⁵ Institute of Genetics and Biophysics A Buzzati-Traverso, CNR, Naples, Italy.
⁶⁶ Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁶⁷ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
⁶⁸ Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Burlo Garofolo', Trieste, Italy.
⁶⁹ University College London Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK.
⁷⁰ Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
⁷¹ Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China.
⁷² Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
⁷³ UChicago Research Bangladesh, Uttara, Dhaka, Bangladesh.
⁷⁴ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
⁷⁵ Metabolic Disease Group, Wellcome Trust Sanger Institute, Cambridge, UK.
⁷⁶ National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷⁷ University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁷⁸ Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁷⁹ Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
⁸⁰ Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
⁸¹ Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore.
⁸² Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁸³ Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁸⁴ Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁸⁵ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
⁸⁶ Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁸⁷ Dayanand Medical College and Hospital Unit, Hero DMC Heart Institute, Ludhiana, India.
⁸⁸ Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.
⁸⁹ Medical Research Center, University of Oulu, Oulu, Finland.
⁹⁰ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁹¹ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁹² Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁹³ Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
⁹⁴ Department of Paediatrics, Yong Loo Lin School of Medicine, Singapore.
⁹⁵ Human Genetics Center, University of Texas School of Public Health at Houston, Houston, Texas, USA.
⁹⁶ University of Southern California Keck School of Medicine, Los Angeles, California, USA.
⁹⁷ Department of Genetics, Chinese National Human Genomic Center, Shanghai, China.
⁹⁸ Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
⁹⁹ Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.
¹⁰⁰ Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
¹⁰¹ Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁰² Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁰³ National Center for Global Health and Medicine, Toyama, Japan.
¹⁰⁴ Duke-National University of Singapore Graduate Medical School, Singapore.
¹⁰⁵ Department of Epidemiology and Public Health, University College London, London, UK.
¹⁰⁶ K.K. Women's and Children's Hospital, Singapore.
¹⁰⁷ University of San Carlos Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.
¹⁰⁸ Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines.
¹⁰⁹ Department of Internal Medicine, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
¹¹⁰ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹¹ Institute of Human Genetics, Technische Universität München, Munich, Germany.
¹¹² Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹³ Department of Medicine I, Ludwig Maximilians University Munich, Munich, Germany.
¹¹⁴ German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
¹¹⁵ Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan.
¹¹⁶ Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹¹⁷ Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.
¹¹⁸ Heart Centre, Department of Cardiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
¹¹⁹ Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.
¹²⁰ Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹²¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹²² Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹²³ Research and Evaluation Division, Bangladesh Rehabilitation Assistance Committee (BRAC), Dhaka, Bangladesh.
¹²⁴ Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå Universitet, Umeå, Sweden.
¹²⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁶ Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
¹²⁷ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
¹²⁸ Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
¹²⁹ Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
¹³⁰ Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
¹³¹ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹³² Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
¹³³ Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
¹³⁴ Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
¹³⁵ Department of Health Science, Shiga University of Medical Science, Otsu, Japan.
¹³⁶ Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
¹³⁷ Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹³⁸ Division of Medicine, Turku University Hospital, Turku, Finland.
¹³⁹ Department of Medicine, University of Turku, Turku, Finland.
¹⁴⁰ Third Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan.
¹⁴¹ Neuroscience and Behavioural Disorders (NBD) Program, Duke-National University of Singapore Graduate Medical School, Singapore.
¹⁴² Duke Eye Center, Duke University Medical Center, Durham, North Carolina, USA.
¹⁴³ Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
¹⁴⁴ Bioinformatics Division, Tsinghua National Laboratory for Informatics Science and Technology (TNLIST), Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.
¹⁴⁵ Center for Synthetic and Systems Biology, TNLIST, Ministry of Education Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.
¹⁴⁶ Department of Psychiatry, University of Hong Kong, Hong Kong.
¹⁴⁷ Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of the Netherlands (ICIN)-Netherlands Heart Institute, Utrecht, the Netherlands.
¹⁴⁸ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁴⁹ William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁵⁰ King Abdulaziz University, Jeddah, Saudi Arabia.
¹⁵¹ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
¹⁵² Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK.
¹⁵³ Hebrew University, School of Public Health, Jerusalem, Israel.
¹⁵⁴ School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁵⁵ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁵⁶ Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁵⁷ ICIN, Utrecht, the Netherlands.
¹⁵⁸ Ministry of Health and Welfare, Seoul, Republic of Korea.
¹⁵⁹ THERAGEN ETEX Bio Institute, Suwon, Republic of Korea.
¹⁶⁰ Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
¹⁶¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁶² Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
¹⁶³ NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
¹⁶⁴ Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
¹⁶⁵ Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan.
¹⁶⁶ Institute of Molecular Genetics, National Research Council (CNR), Pavia, Italy.
¹⁶⁷ Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁶⁸ Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁶⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹⁷⁰ Synlab Academy, Synlab Services, Mannheim, Germany.
¹⁷¹ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷² Department of Genome Science, Aichi-Gakuin University School of Dentistry, Nagoya, Japan.
¹⁷³ National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
¹⁷⁴ Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
¹⁷⁵ Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
¹⁷⁶ Department of Pathology, National University of Singapore, Singapore.
¹⁷⁷ National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
¹⁷⁸ Life Sciences Institute, National University of Singapore, Singapore.
¹⁷⁹ Department of Statistics and Applied Probability, National University of Singapore, Singapore.
¹⁸⁰ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹⁸¹ Imperial College Healthcare NHS Trust, London, UK.

^# Contributed equally.

PMID: 26390057
PMCID: PMC4719169
DOI: 10.1038/ng.3405

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

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Figures

**Figure 1**
Regional plots for the three newly identified loci associated with SBP. Associations of SNPs with SBP in the trans-ancestry GWAS (blue markers; n = 99,994) and of sentinel SNP with methylation at nearby CpG sites (red markers; n = 2,664) are shown. The identities of the sentinel SNP and most closely associated CpG site are provided; correlations between markers are shown in Supplementary Figure 4.

**Figure 2**
Regional plots for the two newly identified loci associated with DBP. Associations of SNPs with DBP in the trans-ancestry GWAS (blue markers; n = 99,994) and of sentinel SNPs with methylation at nearby CpG sites (red markers; n = 2,664) are shown. The identities of the sentinel SNP and most closely associated CpG site are provided; correlations between markers are shown in Supplementary Figure 4.

**Figure 3**
Regional plots for the four newly identified loci associated with pulse pressure. Associations of SNPs with pulse pressure in the trans-ancestry GWAS (blue markers; n = 99,994) and of sentinel SNPs with methylation at nearby CpG sites (red markers; n = 2,664) are shown. The identities of the sentinel SNP and most closely associated CpG site are provided; correlations between SNPs and between methylation markers are shown in Supplementary Figure 4.

**Figure 4**
Regional plots for the three newly identified loci associated with MAP. Associations of SNPs with MAP in the trans-ancestry GWAS (blue markers; n = 99,994) and of sentinel SNPs with methylation at nearby CpG sites (red markers; n = 2,664) are shown. The identities of the sentinel SNP and most closely associated CpG site are provided; correlations between markers are shown in Supplementary Figure 4.

**Figure 5**
DNA methylation as a potential mediator of the relationship between sentinel SNPs and blood pressure at the loci reaching genome-wide significance in our study. Results are shown for the 28 sentinel SNPs that are associated with methylation at P < 0.05 after Bonferroni correction for multiple tests. Predicted effects on blood pressure are based on the relationship of sentinel SNPs with methylation and the relationship of methylation with blood pressure (BP); observed effects represent the direct relationship between the sentinel SNPs and blood pressure (discovery phenotype). The P value is for the correlation of the observed versus predicted effects (solid line).

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References

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1. Imano H, et al. Trends for blood pressure and its contribution to stroke incidence in the middle-aged Japanese population: the Circulatory Risk in Communities Study (CIRCS) Stroke. 2009;40:1571–1577. - PubMed
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1. Forouhi NG, Sattar N, Tillin T, McKeigue PM, Chaturvedi N. Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK. Diabetologia. 2006;49:2580–2588. - PubMed
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

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