Atrial fibrillation (AF) is of major public health importance because of increasing prevalence, and high lifetime risk, costs, morbidity, and mortality. Current AF therapies have partial efficacy, moderate adherence, high cost, and substantial morbidity. Hence, there is a profound need to develop a more comprehensive understanding of the etiology of AF to identify novel approaches to AF management. Genetic data enhance the ability to prioritize pharmaceutical targets for drug discovery programs. We organized and currently lead the only international AF Genetics consortium, AFGen. The Consortium has been highly collegial, extremely productive, and currently consists of investigators from more than 50 studies with >20,000 individuals with AF. AFGen has described the vast majority of genetic loci associated with AF. In recently published work, we have identified a total of 24 AF susceptibility loci in 18K individuals of European and 6 loci in 8K individuals of East Asian ancestry. A major challenge of GWAS has been translating associations at genetic loci into greater mechanistic understandings of disease. In recent work, we have made progress on defining the mechanisms at two of the top AF loci, PITX2 and PRRX1. Despite the progress we made at these loci, a major challenge is that most functional genomic studies are time consuming and have a low throughput. In our renewal application, we propose to extend our ongoing efforts to perform large scale, multi-ethnic WGS and GWAS analyses of AF, and to initiate high throughput functional assays. For our renewal, we propose to combine multiple studies to analyze an AF genome-wide association study (GWAS) consisting of >75K AF cases. By the end of 2018, WGS data also will be available for analyses on ~12K total AF cases within the TOPMed and Centers for Common Disease Genomics projects. Finally, we propose employing our recently piloted massively parallel reporter assays (MPRA), which will allow for testing of all variants at many loci for evidence of enhancer activity in a single experiment. We propose the following Specific Aims: 1. Identify loci and genetic variation related to AF by performing large scale, multi-ethnic GWAS of AF including >75K AF cases and >540K referents. 2. Identify genetic variation related to AF by performing association analyses of WGS data from 12K AF cases and >30K referents from the TOPMed and CCDG sequencing programs. 3. Integrate WGS, GWAS, and MPRA to facilitate functional variant discovery at 25 AF disease loci. Our renewal will enable us to have well-powered, diverse datasets, maximizing our ability to identify common and rare genetic variation underlying AF, and we will conduct critical functional work for AF loci. Our work will provide novel genetic targets for the risk stratification, prevention, and treatment of AF.
Despite affecting ~3 million Americans, relatively little is known about the underlying mechanisms that lead to atrial fibrillation. The goals of the project are to analyze large-scale genetic data for atrial fibrillation to find the causative variants associated with this arrhythmia. Identifying the causal variants will lead to better risk stratification, improved treatment, and potentially the prevention of atrial fibrillation.
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