Abstract 12990: Genome-wide Associations of Global Electrical Heterogeneity ECG Phenotype: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies

Abstract

Introduction: Abnormal myocardial electrophysiological substrate quantified by global electrical heterogeneity (GEH) is independently associated with sudden cardiac death in the general population. The genetic basis of GEH has not been previously studied. Hypothesis: We hypothesized that a genome-wide association study (GWAS) would identify genetic loci related to GEH. Methods: We tested 22-26 million genotyped and imputed variants in African American (AA, N=3,378) and European American (EA, N=12,802) participants in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Five ECG markers of GEH (sum absolute QRST integral (SAI), spatial QRST angle (QRSTA), and spatial ventricular gradient (SVG) magnitude (SVGmag), elevation (SVGel), and azimuth (SVGaz)) were measured on standard 12-lead ECGs. Adjusted linear regression models were constructed with each GEH parameter as an outcome. Results: Ten significant susceptibility loci with 17 SNPs were identified. Multiple GEH parameters were associated with identical SNPs. A low frequency polymorphism (minor allele frequency 0.02) of SCN5A (rs7638275) was strongly associated with SAI (βGWAS -0.30; P=8.71x10 -11 in EA; P=3.49x10 -11 in combined EA/AA). QRSTA, SVGmag, SVGel, and SVGaz were associated with 9 loci, including transcriptional factors ( TBX3, HAND1, NFIA ), implicated in fetal gene program, facilitating molecular remodeling in response to stress. Our strongest association (rs7301677), associated with QRSTA (β GWAS 0.16; P=1.46x10 -26 in the combined EA/AA), was previously reported associated with QRS duration and PR interval, and mapped near the TBX3 gene, which plays a critical role in cardiac conduction system development. Both SAI (P=2.21x10 -10 ) and SVGmag (P=2.40x10 -09 ) were associated with rs7029396 (β GWAS 0.09 in combined EA/AA), mapped near the NCS1 gene, which plays a role in CaMKII-dependent cardiac hypertrophy. SAI was associated with 5 loci; genes in these loci included transcription factors ACTB, SPI-1, IGF1R, GINS3 , and LUZP1 , implicated in cardiac hypertrophy. Conclusions: We identified 10 genetic loci associated with ECG manifestation of GEH. There is a strong association between GEH and genetic signals for molecular remodeling.