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A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

TitleA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.
Publication TypePublication
Year2018
AuthorsSung YJ, Winkler TW, Fuentes Lde Las, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N et al.
Corporate AuthorsCHARGE Neurology Working Group, COGENT-Kidney Consortium, GIANT Consortium, Lifelines Cohort Study
JournalAm J Hum Genet
Volume102
Issue3
Pagination375-400
Date Published2018 03 01
ISSN1537-6605
Keywordsblood pressure, Cohort Studies, Continental Population Groups, Diastole, Epistasis, Genetic, Female, Genetic Loci, genome-wide association study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Smoking, Systole
Abstract

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

DOI10.1016/j.ajhg.2018.01.015
Alternate JournalAm J Hum Genet
PubMed ID29455858
PubMed Central IDPMC5985266
Grant ListU01 AG009740 / AG / NIA NIH HHS / United States
G0700931 / MRC_ / Medical Research Council / United Kingdom
MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom
MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
R01 HL091069 / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
G9521010 / MRC_ / Medical Research Council / United Kingdom
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
MR/K002414/1 / MRC_ / Medical Research Council / United Kingdom
U01 HL130114 / HL / NHLBI NIH HHS / United States
SP/13/2/30111 / BHF_ / British Heart Foundation / United Kingdom
U01 HL120393 / HL / NHLBI NIH HHS / United States
R00 HL130580 / HL / NHLBI NIH HHS / United States
MC_UP_1605/7 / MRC_ / Medical Research Council / United Kingdom
K25 HL121091 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
G0601966 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL118305 / HL / NHLBI NIH HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MR/R023484/1 / MRC_ / Medical Research Council / United Kingdom
R21 HL123677 / HL / NHLBI NIH HHS / United States
MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom
U01 AG023746 / AG / NIA NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
MC_UU_12015/5 / MRC_ / Medical Research Council / United Kingdom
R01 MD012765 / MD / NIMHD NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
P01 CA196569 / CA / NCI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
G0600237 / MRC_ / Medical Research Council / United Kingdom
MS#: 
0482
Manuscript Lead/Corresponding Author Affiliation: 
Affiliated Investigator - Not at HCHS/SOL site
ECI: 
Manuscript Status: 
Published