Abstract TMP99: Genetics Of Stroke Of Undetermined Source: Overlap With Known Stroke Etiologies And Associations With Modifiable Risk Factors

Introduction: Stroke etiology remains unknown in 30% of cases, hindering secondary prevention efforts. We leveraged human genetic data in order to identify evidence of overlap between stroke of undetermined source and defined stroke etiologies as well as causal relationships with modifiable risk factors. Methods: We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls from the NINDS Stroke Genetics Network with TOAST- and CCS-defined subtypes. Using genetic risk scores for large artery, cardioembolic, and small vessel stroke (LAS, CES, SVS) we assessed the degree of overlap with stroke of undetermined source and used pairwise GWAS to search for shared loci. We then applied Mendelian randomization (MR) to identify causal risk factors for stroke of undetermined source. Results: There was significant overlap between stroke of undetermined source and all defined stroke subtypes at a genome-wide and locus level (19 shared loci with LAS, 2 with CES, 5 with SVS). Shared loci pointed to altered gene expression in arterial tissue and blood and atherosclerosis-related mechanisms. Further, genetically predicted carotid intima media thickness was associated with stroke of undetermined source. While genetic liability to atrial fibrillation also showed a significant association, this was attenuated in analyses excluding cases with incomplete diagnostic workup. MR analyses showed significant associations in blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1 levels), and elevated factor XI levels with stroke of undetermined source (Figure). Conclusion: These analyses suggest that stroke of undetermined source shares genetic and modifiable risk factors with defined stroke subtypes. Together, they raise the hypothesis that refinement of current subtyping approaches can reduce the proportion of cases classified as undetermined and optimize secondary prevention strategies.