Abstract 18928: Phenotypic Manifestations of Polygenic Risk for Ischemic Stroke in Adults Free From Disease

Introduction: Ischemic stroke is a complex heritable disease with a substantial proportion of risk attributable to polygenic factors. Little is known about how polygenic risk for stroke may manifest as intermediate phenotypes. Hypothesis: Polygenic liability for ischemic stroke will be associated with cardiometabolic phenotypes even in young adults free from disease. Methods: Polygenic risk derived from a multi ancestry population (GIGASTROKE ~1.2 million SNPs) was applied to 454 White adults from the HERITAGE Family Study with imputed whole genome data available. Participants (mean age = 31.5 ±14.5 years, 51% female) underwent robust cardiometabolic profiling including deeply phenotyped cardiopulmonary exercise tests, body composition, lipid panels, inflammatory markers, and measures of glucose homeostasis. General linear models adjusted for age and sex were used to test the association between z-scored polygenic risk of stroke (SPRS) and 130 phenotypes. A false discovery rate of <5% was used to determine significance. Results: SPRS did not associate with demographic traits or measures of body composition. SPRS was positively associated with several blood pressure related phenotypes with the strongest association between SPRS and systolic blood pressure response to acute exercise (β=0.01, p=2.86e-05), which persisted after adjustment for resting systolic blood pressure. Additionally, 19 total phenotypes were nominally associated (p<0.05) with SPRS including multiple apoB related plasma lipid traits ( Table 1 ). Interestingly, SPRS was also inversely associated with hematocrit (β= -0.06, FDR=0.004). Conclusions: Genetic risk of ischemic stroke is associated with hemodynamic traits even in a cohort of relatively young adults free from overt cardiometabolic disease. Additionally, blood pressure response to acute exercise may represent an early manifestation of genetic liability to stroke.