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

N Loh M Takeuchi F Verweij N Wang X Zhang W Kelly Tn Saleheen D Lehne B Leach Im Drong Aw Abbott J Wahl S Tan St Scott Wr Campanella G Chadeauhyam M Afzal U Ahluwalia Ts Bonder Mj Chen P Dehghan A Edwards Tl Esko T Go Mj Harris Se Hartiala J Kasela S Kasturiratne A Khor Cc Kleber Me Li H Mok Zy Nakatochi M Sapari Ns Saxena R Stewart Af Stolk L Tabara Y Teh Al Wu Y Wu Jy Zhang Y Aits I Da Silva Couto Alves A Das S Dorajoo R Hopewell Jc Kim Yk Koivula Rw Luan J Lyytikäinen Lp Nguyen Qn Pereira Ma Postmus I Raitakari Ot Bryan Ms Scott Ra Sorice R Tragante V Traglia M White J Yamamoto K Zhang Y Adair Ls Ahmed A Akiyama K Asif R Aung T Barroso I Bjonnes A Braun Tr Cai H Chang Lc Chen Ch Cheng Cy Chong Ys Collins R Courtney R Davies G Delgado G Do Ld Doevendans Pa Gansevoort Rt Gao Yt Grammer Tb Grarup N Grewal J Gu D Wander Gs Hartikainen Al Hazen Sl He J Heng Ck Hixson Je Hofman A Hsu C Huang W Husemoen Ll Hwang Jy Ichihara S Igase M Isono M Justesen Jm Katsuya T Kibriya Mg Kim Yj Kishimoto M Koh Wp Kohara K Kumari M Kwek K Lee Nr Lee J Liao J Lieb W Liewald Dc Matsubara T Matsushita Y Meitinger T Mihailov E Milani L Mills R Mononen N Müllernurasyid M Nabika T Nakashima E Ng Hk Nikus K Nutile T Ohkubo T Ohnaka K Parish S Paternoster L Peng H Peters A Pham St Pinidiyapathirage Mj Rahman M Rakugi H Rolandsson O Rozario Ma Ruggiero D Sala Cf Sarju R Shimokawa K Snieder H Sparsø T Spiering W Starr Jm Stott Dj Stram Do Sugiyama T Szymczak S Tang Wh Tong L Trompet S Turjanmaa V Ueshima H Uitterlinden Ag Umemura S Vaarasmaki M Van Dam Rm Van Gilst Wh Van Veldhuisen Dj Viikari Js Waldenberger M Wang Y Wang A Wilson R Wong Ty Xiang Yb Yamaguchi S Ye X Young Rd Young Tl Yuan Jm Zhou X Asselbergs Fw Ciullo M Clarke R Deloukas P Franke A Franks Pw Franks S Friedlander Y Gross Md Guo Z Hansen T Jarvelin Mr Jørgensen T Jukema Jw Kähönen M Kajio H Kivimaki M Lee Jy Lehtimäki T Linneberg A Miki T Pedersen O Samani Nj Sørensen Ti Takayanagi R Toniolo D, Kato; Biosconsortium,; Grampluscd, Cardio; Lifelines Cohort Study,; Interact Consortium Ahsan H Allayee H Chen Yt Danesh J Deary Ij Franco Oh Franke L Heijman Bt Holbrook Jd Isaacs A Kim Bj Lin X Liu J März W Metspalu A Mohlke Kl Sanghera Dk Shu Xo Van Meurs Jb Vithana E Wickremasinghe Ar Wijmenga C Wolffenbuttel Bh Yokota M Zheng W Zhu D Vineis P Kyrtopoulos Sa Kleinjans Jc Mccarthy Mi Soong R Gieger C Scott J Teo Yy He J Elliott P Tai Es Van Der Harst, P Kooner Js Chambers Jc

doi:10.1038/ng.3405

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.