Alteration of the electrocardiographic QT interval and QRS complex reflecting myocardial repolarization and cardiac conduction is associated with arrhythmia, hypertrophy, and sudden cardiac death. The genetic influences that contribute to the underlying biology of these traits remain poorly understood. Understanding disease mechanism is further complicated by the realization that the majority of potential loci identified by genome-wide association studies (GWAS) do not overlap protein-coding genes. Emerging evidence indicates that common variants including single nucleotide polymorphisms (SNPs) reside preferentially in enhancer regions, opening up new possibilities for understanding the contribution of GWAS loci to complex disease. In this proposal, we will provide functional annotation for genetic variants associated with QT/QRS traits using epigenomic maps and test the hypothesis that disruption of enhancer activity by common variants is an important mechanism that contributes to differences in repolarization and conduction traits among individuals. We expect that our work will solve a key limitation in the human genetics field for assigning function to GWAS variants and will potentially identify novel loci, genes, and pathways that can reveal the biological underpinnings of cardiac-related disease and to assess risk of sudden cardiac death. Importantly, our proposal to combine novel computational, genomic, and experimental approaches will provide a platform that can be broadly applied to identify genomic regions and genes associated with any complex human disease.
|Effective start/end date||07/01/2015 → 06/30/2018|