Abstract P650: Increased Genetic Risk for Venous Thromboembolism is Associated With Early Onset Ischemic Stroke

Abstract

Intro: In the Early Onset Stroke Consortium (EOSC) trans-ancestry analysis we found the ABO locus to be strongly associated with early onset stroke (rs529565, OR=1.10, p-value= 2.01 x 10-12). The lead SNP at this locus has a significantly larger effect size in early onset cases compared to stroke cases after age sixty and is independently associated with venous thromboembolism. This finding, in addition with previously reported candidate gene studies ( F5 , F11 , PROCR ), suggests that coagulation and hemostasis related pathways may be a major driver of early onset stroke. Motivation: To examine the genetic relationship between VTE risk burden and early onset stroke, we performed a polygenic risk score analysis to determine whether increased genetic risk for VTE was also more strongly associated with early compared to late age of onset stroke. Methods: Weighted VTE polygenetic risk scores based on recent GWAS of VTE were calculated for each individual in 7K early onset, under age 60, stroke cases from the EOSC and in 9K late onset, ages 60 and older, stroke cases from SiGN. Logistic regression was performed to test the association between the VTE-PRS score and ischemic stroke outcome controlling for sex and the first ten principal components to account for ancestry. Analyses were stratified by age of onset. Fixed effects meta-analysis was performed to combined results across the analysis strata. Results: PRS of VTE was associated with early ischemic stroke (OR=1.11, p-value=0.02) and we saw no association between VTE-PRS and late onset stroke (OR=1.04, p-value=0.5). Early cases had a greater PRS of VTE than late cases (p-value=0.01). Conclusion: While VTE has been shown to associate with stroke risk, we observed a greater genetic risk for VTE in early onset ischemic stroke compared to older onset stroke. This complements existing evidence implicating coagulation-related mechanisms as an important genetic mechanism in early onset strokes.