Fine-mapping and initial characterization of QT interval loci in African Americans.
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.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America. christy_avery@unc.edu
Christy L
CL
Avery
Praveen
P
Sethupathy
Steven
S
Buyske
Qianchuan
Q
He
Dan-Yu
DY
Lin
Dan E
DE
Arking
Cara L
CL
Carty
David
D
Duggan
Megan D
MD
Fesinmeyer
Lucia A
LA
Hindorff
Janina M
JM
Jeff
Liviu
L
Klein
Kristen K
KK
Patton
Ulrike
U
Peters
Ralph V
RV
Shohet
Nona
N
Sotoodehnia
Alicia M
AM
Young
Charles
C
Kooperberg
Christopher A
CA
Haiman
Karen L
KL
Mohlke
Eric A
EA
Whitsel
Kari E
KE
North
D001741:Black or African American; D000368:Aged; D019295:Computational Biology; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D056186:Metagenomics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D013610:Tachycardia / Q000208:ethnology* / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People