Characterizing pleiotropy in cardiometabolic phenotypes among diverse populations

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ABSTRACT Genetic susceptibility underlies a majority of cardiovascular diseases (CVD) and their antecedents, underscored by genome-wide association studies (GWAS) that identified >1,500 loci to-date. Each GWAS-identified locus potentially provides novel mechanistic insight, yet translation of study findings remains largely incomplete, representing a critical barrier to progress. Pleiotropy, a variant that affects multiple phenotypes, is a long- described and pervasive, but largely uncharacterized avenue to advance genomic medicine. Specifically, studies of pleiotropy have the potential to clarify molecular functions, identify mechanistic “common denominators", inform diagnosis and treatment, and prioritize variants for functional interrogation. Systematic and comprehensive interrogation of pleiotropy is particularly relevant for CVD phenotypes, as decades of human and animal studies support a shared genetic architecture that collectively affects downstream clinical disease. Yet, few studies have comprehensively and systematically evaluated pleiotropy within or across cardiovascular phenotypes or extended investigations to examine how pleiotropic variants affect clinical disease. Further, many CVDs and their antecedents disproportionately affect African Americans (AA) and Hispanic/Latinos (HL). However, the majority (>80%) of participants included in GWAS to-date are of European (EU) ancestry. This research disparity creates a biased view of human variation, fails to leverage the unique genetic architecture of AAs and HLs for fine-mapping, and hinders translation of genetic findings into clinical and public health applications relevant for broad populations. We respond to these gaps by leveraging high-quality, harmonized, and centrally available phenotype and genotype data from the Population Architecture Using Genomics in Epidemiology (PAGE) consortium and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=100,917; 35% AA; 32% EU; 24% HL) as well as cutting edge statistical methods to comprehensively identify loci with potential evidence of pleiotropy within and across blood pressure, cholesterol, cardiac conduction, glycemic, inflammatory, and obesity cardiovascular domains as well as incident MI and stroke (Aim 1). At known and novel loci with strong evidence of potential pleiotropy, we will leverage population structure, haplotypic architecture, and phenotype correlation through multi-ethnic, multi-phenotype fine-mapping to prioritize variants for further interrogation (Aim 2). Finally, we will leverage longitudinal data and pathway models to disaggregate variants displaying evidence of biological pleiotropy (i.e. variant affects multiple phenotypes due to shared biology) from variants displaying evidence of mediated pleiotropy (e.g. variant influences one phenotype and this phenotype influences a second phenotype) (Aim 3). We hypothesize that CVD phenotypes and clinical disease may be more accurately characterized as variations in clinical expression, with common biological mechanisms. By investigating pleiotropy, we hope to clarify these mechanisms, which has the potential to inform phenotype classification, drug development and repurposing, and CVD prevention.