PR间期(PR)是心房和房室结传导的可遗传心电图测量。PR持续时间的变化可能与心房颤动有关,心力衰竭和全因死亡率。西班牙裔/拉丁裔人口有很高的心血管发病率和死亡率负担,高度混合,代表了新基因座鉴定的特殊机会。然而,他们仍然长期被低估。我们从三项研究中对14756名西班牙裔/拉丁美洲裔参与者进行了首次PR全基因组关联研究(GWAS)。
1000个基因组1期估算的单核苷酸多态性(SNP)与PR之间的关联的特定研究摘要结果假定为加性遗传模型,并针对全球血统进行了调整。研究中心/地区和临床协变量。结果使用固定效应组合,逆方差加权荟萃分析。顺序条件分析用于鉴定独立信号。在亚洲人群中进行了新基因座的复制,非洲和欧洲血统。ENCODE和RoadMap数据用于注释结果。
我们发现了一种新的全基因组关联(P<5×10-8)与ID2处的PR(rs6730558),在亚洲和欧洲人群中复制(P<0.017)。此外,我们将10个先前鉴定的PR基因座推广到西班牙裔/拉丁裔。生物信息学注释为心脏组织的调节功能提供了证据。Further,对于六个广义的基因座,西班牙裔/拉丁裔指数SNP具有全基因组显著性,并且与先前鉴定的GWAS前导SNP相同(或高度连锁不平衡).
我们的结果表明,PR的遗传决定因素在种族/民族之间是一致的,但是将研究扩展到混合人群可以识别新的关联,强调在不同人群中进行遗传研究的重要性。
PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association
study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies.
Study-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry,
study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results.
We identified a novel genome-wide association (P<5×10-8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP.
Our results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.