Abstract 14154: Genome-Wide Association Study of Dilated Cardiomyopathy in the VA Million Veteran Program

Abstract

Introduction: Rare, Mendelian drivers of dilated cardiomyopathy (DCM) are well-established, but the contribution of common genetic variation to DCM risk has emerged more recently. As common variant discovery has largely relied on genome wide association studies (GWAS) of prospectively recruited DCM cases, we sought to conduct a GWAS of retrospectively-defined DCM from a large biobank. Methods: We used electronic health record-based phenotyping to define DCM in the VA Million Veteran Program (MVP), performed ancestry-specific GWAS in MVP participants of European and African genetic ancestry, and then conducted a trans-ethnic meta-analysis. We pursued replication of sentinel DCM single nucleotide polymorphisms (SNPs) in the UK Biobank. We further assessed the association of sentinel DCM SNPs with subclinical cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function in UK Biobank, and with hypertrophic cardiomyopathy (HCM) in MVP. Results: Among 459,937 MVP study participants, mean age was 61.5, 43,971 (9.6%) were female, and 5,597 had DCM (N=3,786 European ancestry, N=1,811 African ancestry). In trans-ethnic meta-analysis, we identified eight genomic regions associated with DCM at genome-wide significance (P < 5x10 -8 ). These included three of four known DCM associations near HSPB7 , LSM3 , and BAG3 ; and five novel genomic regions near SLC39A8 , CDKN1A , CD36 , NEDD4L , and MAP3K7CL . Three of the novel regions (at CDKN1A , NEDD4L , and MAP3K7CL ) were replicated in UK Biobank (all p<8.0E-4; N=899 DCM cases, 449,574 controls). SNPs associated with increased DCM risk also associated with increased LV end-diastolic and end-systolic volumes and lower LV ejection fraction in UK Biobank participants without clinical heart failure or cardiomyopathy (N > 31,614; all p < 0.01). Sentinel SNPs for DCM also showed a trend towards an opposite direction of association with HCM in MVP (N=1,533 HCM cases, 465,877 controls). Conclusions: We conducted the largest GWAS of DCM to date, and identified five novel, common genetic loci associated with DCM with replication of three novel loci in an external cohort. Our findings highlight the potential to leverage emerging biobank populations to scale common variant discovery for DCM.