Multi-Cohort Analysis Reveals Genetic Predispositions to Clonal Hematopoiesis as Mutation-Specific Risk Factors for Stroke

Abstract

Recent observational studies have found an association between Clonal Hematopoesis (CH) and strokes but with incomplete results. This study aims to comprehensively characterize mutation-specific effects of CH on ischemic and hemorrhagic stroke subtypes and 90-day functional outcomes through publicly available genome-wide association study (GWAS) cohorts and Mendelian Randomization. TET2 is associated with an increased risk of overall stroke (OR = 1.06, P = 0.02), ischemic stroke (OR = 1.05, P = 0.03), transient ischemic attack (OR = 1.07, P = 0.01) and small vessel stroke (OR = 1.29, P = 0.01), as well as adverse 90-day modified Rankin scale (mRS ≥ 3) before (OR = 1.34, P = 0.005) and after adjusted for age, sex, and stroke severity (OR = 1.30, P = 0.02). While the presence of any CH mutation is associated with intracerebral hemorrhage (ICH) (OR = 1.21, P = 0.02), specific mutations, SRSF2 and ASXL1 are protective against ICH (OR = 0.9, P = 0.04) and nontraumatic subarachnoid hemorrhage (OR = 0.92, P = 0.03), respectively. In conclusion, the study provided genetic evidence that TET2 is strongly associated with an increased risk of ischemic stroke and poor functional recovery. Future studies clarifying the relationship between CH and hemorrhagic stroke subtypes are needed.