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

被引：267

作者：

Kato, Norihiro ^{[1
]}

Loh, Marie ^{[2
,3
,4
]}

Takeuchi, Fumihiko ^{[1
]}

Verweij, Niek ^{[5
]}

Wang, Xu ^{[6
,7
]}

Zhang, Weihua ^{[3
,8
]}

Kelly, Tanika N. ^{[9
]}

Saleheen, Danish ^{[10
,11
,12
]}

Lehne, Benjamin ^{[3
]}

Leach, Irene Mateo ^{[5
]}

Drong, Alexander W. ^{[13
]}

Abbott, James ^{[14
]}

Wahl, Simone ^{[15
,16
,17
]}

Tan, Sian-Tsung ^{[8
,18
]}

Scott, William R. ^{[3
,18
]}

Campanella, Gianluca ^{[3
]}

Chadeau-Hyam, Marc ^{[3
]}

Afzal, Uzma ^{[3
,8
]}

Ahluwalia, Tarunveer S. ^{[19
,20
,21
]}

Bonder, Marc Jan ^{[22
]}

Chen, Peng ^{[6
,7
]}

Dehghan, Abbas ^{[23
]}

Edwards, Todd L. ^{[24
]}

Esko, Tonu ^{[25
,26
,27
,28
]}

Go, Min Jin ^{[29
]}

Harris, Sarah E. ^{[30
,31
,32
]}

Hartiala, Jaana ^{[33
,34
]}

Kasela, Silva ^{[25
]}

Kasturiratne, Anuradhani ^{[35
]}

Khor, Chiea-Chuen ^{[6
,7
,36
,37
,38
]}

Kleber, Marcus E. ^{[39
]}

Li, Huaixing ^{[40
]}

Mok, Zuan Yu ^{[41
]}

Nakatochi, Masahiro ^{[42
]}

Sapari, Nur Sabrina ^{[41
]}

Saxena, Richa ^{[43
]}

Stewart, Alexandre F. R. ^{[44
,45
]}

Stolk, Lisette ^{[46
]}

Tabara, Yasuharu ^{[47
]}

Teh, Ai Ling ^{[48
]}

Wu, Ying ^{[49
]}

Wu, Jer-Yuarn ^{[50
,51
]}

Zhang, Yi ^{[52
,53
]}

Aits, Imke ^{[54
]}

Alves, Alexessander Da Silva Couto ^{[55
]}

Das, Shikta ^{[55
]}

Dorajoo, Rajkumar ^{[36
]}

Hopewell, Jemma C. ^{[56
]}

Kim, Yun Kyoung ^{[29
]}

Koivula, Robert W. ^{[57
]}

机构：

[1] Natl Ctr Global Hlth & Med, Res Inst, Dept Gene Diagnost & Therapeut, Tokyo, Japan

[2] Univ Oulu, Inst Hlth Sci, Oulu, Finland

[3] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England

[4] ASTAR, Translat Lab Genet Med, Singapore, Singapore

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[6] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore

[7] Natl Univ Hlth Syst, Singapore, Singapore

[8] Ealing Hosp Natl Hlth Serv NHS Trust, Southall, Middx, England

[9] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA

[10] Ctr Non Communicable Dis, Karachi, Pakistan

[11] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England

[12] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[13] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[14] Univ London Imperial Coll Sci Technol & Med, Bioinformat Support Serv, London, England

[15] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[16] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany

[17] German Ctr Diabet Res DZD, Neuherberg, Germany

[18] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[19] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[20] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood COSP, Copenhagen, Denmark

[21] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[22] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[23] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[24] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr,Ctr Human Genet Res, Nashville, TN USA

[25] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[26] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[27] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[28] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[29] Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea

[30] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[31] Western Gen Hosp, Inst Genet & Mol Med, MRC, Edinburgh EH4 2XU, Midlothian, Scotland

[32] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[33] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[34] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA

[35] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka

[36] ASTAR, Genome Inst Singapore, Singapore, Singapore

[37] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore

[38] Natl Univ Singapore, Dept Paediat, Singapore 117548, Singapore

[39] Heidelberg Univ, Mannheim Med Fac, Med Clin V, Mannheim, Germany

[40] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai, Peoples R China

[41] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore

[42] Nagoya Univ Hosp, Ctr Adv Med & Clin Res, Nagoya, Aichi, Japan

[43] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA

[44] Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr, Ottawa, ON, Canada

[45] Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada

[46] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[47] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[48] ASTAR, Singapore Inst Clin Sci, Singapore, Singapore

[49] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[50] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan

来源：

NATURE GENETICS | 2015年 / 47卷 / 11期

基金：

中国国家自然科学基金; 新加坡国家研究基金会; 英国生物技术与生命科学研究理事会; 英国医学研究理事会; 芬兰科学院; 美国国家卫生研究院; 瑞典研究理事会; 英国惠康基金;

关键词：

RISK-FACTORS; REGIONS; DISEASE; KIDNEY; METAANALYSIS; INDIVIDUALS; PERFORMANCE; POPULATION; EXPRESSION; VARIANTS;

D O I：

10.1038/ng.3405

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-11) to 5.0 x 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 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

引用

页码：1282 / +

页数：14

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