Atrial fibrillation (AF) will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, hypertension, diabetes and obesity. Previously, heritable forms of AF have been considered rare; yet in the last decade, we established that AF, and in particular early-onset forms of AF, are heritable. In 2008, we organized the AFGen Consortium which currently consists of investigators from more than 50 studies with >60,000 individuals with AF and >600,000 without AF. Our Consortium has led the field of AF genetics, describing the vast majority of genetic loci associated with AF. Interestingly, despite typically having a greater burden of AF risk factors, individuals of African, Asian and Hispanic ethnicity/ancestry consistently have been reported to have a lower risk of AF in clinical and genetic studies. While the ranges vary, it is apparent that even under conservative of assumptions the prevalence of AF in individuals of African ancestry is roughly half that of individuals of European ancestry. The goals of the current proposal will be to further define the genetic basis of AF in African-Americans and to use this information to refine the genetic risk of AF and aid in the discovery of AF related genetic variation. Specifically, we propose to:1. Perform the largest GWAS to date of African American individuals consisting of over 3,000 cases and >10,000 controls to enable a) admixture mapping, b) refinement of known AF loci, and c) identification of new AF loci.2. Develop ancestry specific risk scores for individuals of non-European ancestry that borrow information from our current, primarily European-ancestry GWAS.3. Identify causative genes at AF GWAS loci by a) creating an epigenomic map of the human left atrium, b) integrating the epigenomic map and AF genetic data to prioritize target genes at AF loci and c) validating the function of AF target genes in stem cell derived cardiomyocytes.Ultimately, we hope that our approach will provide novel genetic targets for the risk stratification, prevention, and treatment of this common and morbid arrhythmia.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|