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Fine-mapping and initial characterization of QT interval loci in African Americans.

TitleFine-mapping and initial characterization of QT interval loci in African Americans.
Publication TypeJournal Article
Year of Publication2012
AuthorsAvery CL, Sethupathy P, Buyske S, He Q, Lin D-Y, Arking DE, Carty CL, Duggan D, Fesinmeyer MD, Hindorff LA, Jeff JM, Klein L, Patton KK, Peters U, Shohet RV, Sotoodehnia N, Young AM, Kooperberg C, Haiman CA, Mohlke KL, Whitsel EA
Secondary AuthorsNorth KE
JournalPLoS Genet
Volume8
Issue8
Paginatione1002870
Date Published2012
ISSN1553-7404
KeywordsAfrican Americans, Aged, Computational Biology, Electrocardiography, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors, Tachycardia, United States
Abstract

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

DOI10.1371/journal.pgen.1002870
Alternate JournalPLoS Genet
PubMed ID22912591
PubMed Central IDPMC3415454
Grant ListN01WH42124 / WH / WHI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
N01WH32102 / WH / WHI NIH HHS / United States
R00 HL098458 / HL / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
N01WH42112 / WH / WHI NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
N01WH42119 / WH / WHI NIH HHS / United States
U01 HL65520 / HL / NHLBI NIH HHS / United States
N01-HV-48195 / HV / NHLBI NIH HHS / United States
N01WH32112 / WH / WHI NIH HHS / United States
N01WH32101 / WH / WHI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
U01 HL65521 / HL / NHLBI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
N01WH32119 / WH / WHI NIH HHS / United States
N01WH32105 / WH / WHI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01WH42132 / WH / WHI NIH HHS / United States
U01 HG007416 / HG / NHGRI NIH HHS / United States
N01WH42121 / WH / WHI NIH HHS / United States
U01 HL41642 / HL / NHLBI NIH HHS / United States
N01WH42113 / WH / WHI NIH HHS / United States
N01WH42125 / WH / WHI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R00HL098458 / HL / NHLBI NIH HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01WH32106 / WH / WHI NIH HHS / United States
N01WH42129 / WH / WHI NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
N01WH42108 / WH / WHI NIH HHS / United States
N01WH42118 / WH / WHI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01-HC-15103 / HC / NHLBI NIH HHS / United States
N01WH32113 / WH / WHI NIH HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
U01 HL41654 / HL / NHLBI NIH HHS / United States
N01WH42120 / WH / WHI NIH HHS / United States
N01WH32118 / WH / WHI NIH HHS / United States
HL088456 / HL / NHLBI NIH HHS / United States
R25 GM062459 / GM / NIGMS NIH HHS / United States
N01WH42131 / WH / WHI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01WH42109 / WH / WHI NIH HHS / United States
N01-HC-45134 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01WH42114 / WH / WHI NIH HHS / United States
U01 HL41652 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01WH32122 / WH / WHI NIH HHS / United States
N01WH42107 / WH / WHI NIH HHS / United States
1K99DK091318-01 / DK / NIDDK NIH HHS / United States
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N01-HC-48049 / HC / NHLBI NIH HHS / United States
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N01WH42130 / WH / WHI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01WH42117 / WH / WHI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01WH42115 / WH / WHI NIH HHS / United States
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R37CA54281 / CA / NCI NIH HHS / United States
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N01WH32108 / WH / WHI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
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N01-HC-85079 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
N01WH42122 / WH / WHI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
N01WH32100 / WH / WHI NIH HHS / United States
N01-HC-48048 / HC / NHLBI NIH HHS / United States
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N01-HC-55018 / HC / NHLBI NIH HHS / United States
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