The QT interval (QT) is a heritable trait and its prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Most genetic studies of QT have examined populations of European ancestry, although the increased genetic diversity in populations of African descent provides opportunity for fine-mapping, which can help narrow association signals and identify candidates for functional characterization. We examined whether eleven previously identified QT loci comprising 6,681 variants on the Illumina Metabochip array were associated with QT in 7,516 African American participants from the Atherosclerosis Risk in Communities study and Women’s Health Initiative clinical trial. Among associated loci, we used conditional analyses and queried bioinformatics databases to identify and functionally categorize signals. We identified nine of the eleven QT loci in African American populations (
P
<0.0045 under an additive genetic model adjusting for ancestry and demographic characteristics:
NOS1AP, ATP1B1, SCN5A, SLC35F1, KCNH2, KCNQ1, LITAF, NDRG4,
and
RFFL
). We also identified two independent secondary signals in
NOS1AP
and
ATP1B1
(
P
< 7.4x10
−6
). Conditional analyses adjusting for published loci in European populations demonstrated that eight of these eleven SNPs (nine primary; two secondary) were independent of previously reported SNPs. We then performed the first bioinformatics-based functional characterization of QT loci using the eleven primary and secondary variants and SNPs in strong LD (r
2
> 0.5) among these African American participants. Only the
SCN5A
locus included a non-synonymous coding variant (rs1805124, H558R, r
2
= 0.7 with primary SNP rs9871385,
P
= 4.7x10
−4
). The remaining ten loci harbored variants located exclusively within non-coding regions. Specifically, three contained SNPs within candidate long-range regulatory elements in human cardiomyocytes, five were in or near annotated promoter regions, and the remaining two were in un-annotated, but highly conserved non-coding elements. Several of the QT risk alleles at these SNPs significantly alter the predicted binding affinity for transcription factors, such as TBX5 and AhR, which have been previously implicated in cardiac formation and function. In summary, the findings provide compelling evidence that the same genes influence variation in QT across global populations and that additional, independent signals exist in African Americans. Moreover, of those SNPs identified as strong candidates for functional evaluation, the majority implicate gene regulatory dysfunction in QT prolongation.
Characterization of the non-linear rate-dependency of QT interval in humans
