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

Nat Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
11
Pages
1282-93
Date Published
2015 11
ISSN
1546-1718
URL
DOI
10.1038/ng.3405
PubMed ID
26390057
PubMed Central ID
PMC4719169
Links
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ETM/55 / Chief Scientist Office / United Kingdom
R01 DK080720 / DK / NIDDK NIH HHS / United States
2R01LM010098 / LM / NLM NIH HHS / United States
G0500539 / MRC / United Kingdom
DK078150 / DK / NIDDK NIH HHS / United States
CZB/4/505 / Chief Scientist Office / United Kingdom
R01 ES021801 / ES / NIEHS NIH HHS / United States
G0800270 / Medical Research Council / United Kingdom
R01HL087263 / HL / NHLBI NIH HHS / United States
084723/Z/08/Z / Wellcome Trust / United Kingdom
R01 MH063706 / MH / NIMH NIH HHS / United States
R01HL103866 / HL / NHLBI NIH HHS / United States
RG/13/2/30098 / British Heart Foundation / United Kingdom
P30 ES010126 / ES / NIEHS NIH HHS / United States
MR/K002414/1 / Medical Research Council / United Kingdom
G0600331 / Medical Research Council / United Kingdom
R01 HL036310 / HL / NHLBI NIH HHS / United States
G0902037 / MRC / United Kingdom
TW008288 / TW / FIC NIH HHS / United States
R01 HL103931 / HL / NHLBI NIH HHS / United States
R01 CA082729 / CA / NCI NIH HHS / United States
SP/04/002 / British Heart Foundation / United Kingdom
R01 HL087679 / HL / NHLBI NIH HHS / United States
5R01AG13196 / AG / NIA NIH HHS / United States
R01CA144034 / CA / NCI NIH HHS / United States
R35CA53890 / CA / NCI NIH HHS / United States
R01ES021801 / ES / NIEHS NIH HHS / United States
G0700931 / Medical Research Council / United Kingdom
R37 CA070867 / CA / NCI NIH HHS / United States
RG/08/014/24067 / British Heart Foundation / United Kingdom
R01HL090682 / HL / NHLBI NIH HHS / United States
R01CA55069 / CA / NCI NIH HHS / United States
R01 HL103866 / HL / NHLBI NIH HHS / United States
084723 / Wellcome Trust / United Kingdom
5R01MH63706:02 / MH / NIMH NIH HHS / United States
R01 CA144034 / CA / NCI NIH HHS / United States
SP/09/002 / British Heart Foundation / United Kingdom
Biotechnology and Biological Sciences Research Council / United Kingdom
G0902037 / Medical Research Council / United Kingdom
1RL1MH083268-01 / MH / NIMH NIH HHS / United States
R01CA82729 / CA / NCI NIH HHS / United States
UM1 CA173640 / CA / NCI NIH HHS / United States
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MR/L01341X/1 / Medical Research Council / United Kingdom
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MR/L003120/1 / Medical Research Council / United Kingdom
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MC_UU_12015/1 / Medical Research Council / United Kingdom
TW05596 / TW / FIC NIH HHS / United States
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P42 ES010349 / ES / NIEHS NIH HHS / United States
MC_U106179471 / Medical Research Council / United Kingdom
DK56350 / DK / NIDDK NIH HHS / United States
R01 DK082766 / DK / NIDDK NIH HHS / United States
RR20649 / RR / NCRR NIH HHS / United States
G0800270 / MRC / United Kingdom
HL085144 / HL / NHLBI NIH HHS / United States
R01HL103931 / HL / NHLBI NIH HHS / United States
R35 CA053890 / CA / NCI NIH HHS / United States
P01 HL098055 / HL / NHLBI NIH HHS / United States
R37CA70867 / CA / NCI NIH HHS / United States
R01 CA055069 / CA / NCI NIH HHS / United States
RG/07/008/23674 / British Heart Foundation / United Kingdom
P01HL076491 / HL / NHLBI NIH HHS / United States
G0802782 / Medical Research Council / United Kingdom
MC_UU_12013/1 / Medical Research Council / United Kingdom
R01 CA107431 / CA / NCI NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
R01 LM010098 / LM / NLM NIH HHS / United States
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N0T-HG-11-009 / HG / NHGRI NIH HHS / United States
G0600331 / MRC / United Kingdom
R01 CA080205 / CA / NCI NIH HHS / United States
R01 HL087263 / HL / NHLBI NIH HHS / United States
U01 HL072507 / HL / NHLBI NIH HHS / United States
R01 HL085144 / HL / NHLBI NIH HHS / United States
MR/K013351/1 / Medical Research Council / United Kingdom
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G51 / Action on Hearing Loss / United Kingdom
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UM1CA173640 / CA / NCI NIH HHS / United States
P30 DK056350 / DK / NIDDK NIH HHS / United States
R01 TW008288 / TW / FIC NIH HHS / United States
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
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BB/F019394/1 / Biotechnology and Biological Sciences Research Council / United Kingdom
RL1 MH083268 / MH / NIMH NIH HHS / United States
R01DK082766 / DK / NIDDK NIH HHS / United States
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UM1 CA182910 / CA / NCI NIH HHS / United States
FS/14/55/30806 / British Heart Foundation / United Kingdom
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MR/M012638/1 / Medical Research Council / United Kingdom