Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans

Abstract

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations Swenson Hispanic/Latino QRS GWAS

“…Our GWAS meta-analysis of four cohorts containing 15,124 individuals of Hispanic/Latino ethnicity found 9 index SNPs across 6 loci with genome-wide significant associations with QRS duration. Two loci were novel (MYOCD and SYT1) and four of the loci (SCN5A-SCN10A, CDKN1A, HAND1, and VTI1A) were previously identified in QRS GWAS analyses of European- (11) and African-descent (17) individuals. This is the first GWAS of QRS duration in Hispanics/Latinos, a genetically admixed group, comprised of European, African, and Native American ancestry populations, for whom genetic as well as non-genetic determinants of cardiovascular risk remain underexamined (22,23).…”

“…We examined association of 32 index SNPs from published GWAS analyses (27 European,1 African-American, 2 East Asian, and 2 from a meta-analysis of the European and African American GWAS results) for association with QRS duration among Hispanics/Latinos (11,13,17) (Supplementary Table 8, Figure 4). Of the 32 previously identified independent SNPs, 27 generalized in Hispanics/Latinos (r-value <0.05).…”

“…African American (n=13,301) ancestries. Details of these studies can be obtained from their original publications (11,17).…”

“…To date, heritability estimates of QRS duration have varied with up to ~40% heritability found in more recent studies (6)(7)(8)(9). While previous genome-wide association studies have predominantly focused on European populations (10)(11)(12), there have been several smaller studies of Asian (13,14), Pacific Islander (15), and African American populations (16,17). Collectively, these GWAS analyses have identified 32 SNPs across 26 loci associated with QRS duration.…”

“…Collectively, these GWAS analyses have identified 32 SNPs across 26 loci associated with QRS duration. These loci harbor ion channel and transcription factor genes involved in cardiac conduction, including SCN5A, SCN10A, TBX3, TBX5, TBX20, and HAND1 (10)(11)(12)(13)(14)(15)(16)(17). To our knowledge, there has been no GWAS performed to study the genetics of QRS duration in Hispanic/Latino ancestry populations.…”