Abstract WP304: Genomic and Electronic Health Record-Based Evaluation of Known Ischemic Stroke Susceptibility Genes in the <i>All of Us</i> Research Program

Introduction: Ischemic strokes arise from a complex interplay of genetic and environmental factors, including age and smoking. Prior case-control and meta-analyses have identified five genes ( ALOX5AP, F2, F5, NOS3, PRKCH ) involved in vascular pathways that may increase ischemic stroke susceptibility. Objective: To assess whether ischemic stroke and related phenotypes can be captured using these genetic associations by leveraging genomic and electronic health record (EHR) data from the All of Us Research Program ( All of Us ). Methods: We constructed a cohort from All of Us (v8) containing participants with pathogenic/likely pathogenic (P/LP) variants in the five-gene set (n=244) and compared them to all others. Cardiovascular and circulatory phenotypes were assessed using phenome-wide association studies (PheWAS) and Kaplan–Meier survival analysis for time-to-stroke. Results: Participants with P/LP variants did not show stronger associations with stroke or ischemic stroke-related phecodes than the broader cohort. Ischemic stroke (OR=1.34, p=0.49), transient cerebral ischemic attack (OR=1.78, p=0.26), and occlusion and stenosis of cerebral arteries (OR=2.94, p=0.13) were non-significant, as were stroke (OR=1.39, p=0.40) and combined stroke and transient ischemic attack (OR=1.70, p=0.066). Several upstream risk factors achieved nominal significance, including atrial flutter (OR=2.55, p=0.044), heart failure (OR=1.80, p=0.025), peripheral vascular disease (OR=1.95, p=0.036), and embolism and thrombosis (OR=1.94, p=8.13e-3). Hypertension (OR=1.36, p=0.102) was non-significant, though hemorrhagic stroke-related phecodes, such as nontraumatic subdural hemorrhage (OR=5.03, p=0.025), were nominally significant. Kaplan–Meier curves suggested earlier ischemic stroke onset, but differences were not statistically significant. Demographics (age, race, sex) and EHR covariates (record length, ICD code counts) were similar between groups. Conclusion: All of Us identified nominal associations between the ischemic stroke gene set and upstream cardiovascular risk factors but no strong genetic association with ischemic stroke itself. Findings may reflect limited gene penetrance, underrepresentation of stroke events in the cohort, or both. Larger, longitudinally enriched datasets and broader variant sets are needed to fully assess genetic risk and better capture late-onset events.