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, 47 (11), 1282-1293

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 Drong  12 James Abbott  13 Simone Wahl  14   14   15 Sian-Tsung Tan  7   16 William R Scott  3   16 Gianluca Campanella  3 Marc Chadeau-Hyam  3 Uzma Afzal  3   7 Tarunveer S Ahluwalia  17   18   19 Marc Jan Bonder  20 Peng Chen  6 Abbas Dehghan  21 Todd L Edwards  22 Tõnu Esko  23   24   25   26 Min Jin Go  27 Sarah E Harris  28   29 Jaana Hartiala  30   31 Silva Kasela  23 Anuradhani Kasturiratne  32 Chiea-Chuen Khor  6   33   34   35 Marcus E Kleber  36 Huaixing Li  37 Zuan Yu Mok  38 Masahiro Nakatochi  39 Nur Sabrina Sapari  38 Richa Saxena  40 Alexandre F R Stewart  41   42 Lisette Stolk  43 Yasuharu Tabara  44 Ai Ling Teh  45 Ying Wu  46 Jer-Yuarn Wu  47   48 Yi Zhang  49   50 Imke Aits  51 Alexessander Da Silva Couto Alves  52 Shikta Das  52 Rajkumar Dorajoo  33 Jemma C Hopewell  53 Yun Kyoung Kim  27 Robert W Koivula  54 Jian'an Luan  55 Leo-Pekka Lyytikäinen  56   57 Quang N Nguyen  58 Mark A Pereira  59 Iris Postmus  60   61 Olli T Raitakari  62   63 Molly Scannell Bryan #  64 Robert A Scott  55 Rossella Sorice  65 Vinicius Tragante  66 Michela Traglia  67   68 Jon White  69 Ken Yamamoto  70 Yonghong Zhang  71 Linda S Adair  72 Alauddin Ahmed  73 Koichi Akiyama  1 Rasheed Asif  9 Tin Aung  74 Inês Barroso  75   76   77 Andrew Bjonnes  40 Timothy R Braun  78 Hui Cai  79   80 Li-Ching Chang  47 Chien-Hsiun Chen  47   48 Ching-Yu Cheng  6   34   74   81 Yap-Seng Chong  45   82 Rory Collins  53 Regina Courtney  79   80 Gail Davies  29   83 Graciela Delgado  36 Loi D Do  58 Pieter A Doevendans  66 Ron T Gansevoort  84 Yu-Tang Gao  85 Tanja B Grammer  36 Niels Grarup  17 Jagvir Grewal  3   7 Dongfeng Gu  86 Gurpreet S Wander  87 Anna-Liisa Hartikainen  88   89   90 Stanley L Hazen  91   92 Jing He  93 Chew-Kiat Heng  94 James E Hixson  95 Albert Hofman  21 Chris Hsu  96 Wei Huang  97 Lise L N Husemoen  98 Joo-Yeon Hwang  27 Sahoko Ichihara  99 Michiya Igase  100 Masato Isono  1 Johanne M Justesen  17 Tomohiro Katsuya  101   102 Muhammad G Kibriya  64 Young Jin Kim  27 Miyako Kishimoto  103 Woon-Puay Koh  6   104 Katsuhiko Kohara  100 Meena Kumari  105 Kenneth Kwek  106 Nanette R Lee  107   108 Jeannette Lee  6 Jiemin Liao  34   74 Wolfgang Lieb  51 David C M Liewald  29   83 Tatsuaki Matsubara  109 Yumi Matsushita  103 Thomas Meitinger  110   111 Evelin Mihailov  23 Lili Milani  23 Rebecca Mills  7 Nina Mononen  56   57 Martina Müller-Nurasyid  112   113   114 Toru Nabika  115 Eitaro Nakashima  116   117 Hong Kiat Ng  38 Kjell Nikus  118 Teresa Nutile  65 Takayoshi Ohkubo  119 Keizo Ohnaka  120 Sarah Parish  53 Lavinia Paternoster  121 Hao Peng  71 Annette Peters  122   114 Son T Pham  58 Mohitha J Pinidiyapathirage  32 Mahfuzar Rahman  73   123 Hiromi Rakugi  102 Olov Rolandsson  124 Michelle Ann Rozario  38 Daniela Ruggiero  65 Cinzia F Sala  67 Ralhan Sarju  87 Kazuro Shimokawa  1 Harold Snieder  125 Thomas Sparsø  17 Wilko Spiering  126 John M Starr  29   127 David J Stott  128 Daniel O Stram  96 Takao Sugiyama  129 Silke Szymczak  130 W H Wilson Tang  91   131 Lin Tong  64 Stella Trompet  132 Väinö Turjanmaa  133   134 Hirotsugu Ueshima  135   136 André G Uitterlinden  21   43 Satoshi Umemura  137 Marja Vaarasmaki  88   89   90 Rob M van Dam  6 Wiek H van Gilst  5 Dirk J van Veldhuisen  5 Jorma S Viikari  138   139 Melanie Waldenberger  14   122 Yiqin Wang  37 Aili Wang  71 Rory Wilson  14   122 Tien-Yin Wong  34   74 Yong-Bing Xiang  85 Shuhei Yamaguchi  140 Xingwang Ye  37 Robin D Young  10 Terri L Young  141   142 Jian-Min Yuan  143 Xueya Zhou  144   145   146 Folkert W Asselbergs  66   147   148 Marina Ciullo  65 Robert Clarke  53 Panos Deloukas  149   150 Andre Franke  130 Paul W Franks  54   124   151 Steve Franks  152 Yechiel Friedlander  153 Myron D Gross  154 Zhirong Guo  71 Torben Hansen  17 Marjo-Riitta Jarvelin  2   52   90   155   156 Torben Jørgensen  98 J Wouter Jukema  132   147   157 Mika Kähönen  133   134 Hiroshi Kajio  103 Mika Kivimaki  105 Jong-Young Lee  158   159 Terho Lehtimäki  56   57 Allan Linneberg  98   160   161 Tetsuro Miki  100 Oluf Pedersen  17 Nilesh J Samani  162   163 Thorkild I A Sørensen  17   121   164 Ryoichi Takayanagi  165 Daniela Toniolo  67   166 BIOS-consortiumCARDIo GRAMplusCDLifeLines Cohort StudyInterAct ConsortiumHabibul Ahsan  64 Hooman Allayee  30   31 Yuan-Tsong Chen  47 John Danesh  10   167 Ian J Deary  29   83 Oscar H Franco  21 Lude Franke  20 Bastiaan T Heijman  168 Joanna D Holbrook  45 Aaron Isaacs  21 Bong-Jo Kim  27 Xu Lin  37 Jianjun Liu  6   33 Winfried März  36   169   170 Andres Metspalu  23 Karen L Mohlke  46 Dharambir K Sanghera  78 Xiao-Ou Shu  79   80 Joyce B J van Meurs  43 Eranga Vithana  34   74   141 Ananda R Wickremasinghe  32 Cisca Wijmenga  20 Bruce H W Wolffenbuttel  171 Mitsuhiro Yokota  172 Wei Zheng  79   80 Dingliang Zhu  49   50 Paolo Vineis  3 Soterios A Kyrtopoulos  173 Jos C S Kleinjans  174 Mark I McCarthy  12   175 Richie Soong  38   176 Christian Gieger  14   122 James Scott  16 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

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.

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.

Figures

Figure 1
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
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
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
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
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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