Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke

Abstract

Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03–1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08–1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95–1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.

Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke

“…It is also possible that other acquired structural chromosomal alterations and mutations that can co-occur with LOY, and reflect genomic instability, contribute to our findings. In support for such a hypothesis, we found associations for the polygenic risk score for LOY and stroke outcome in both sexes, 6 and similar findings have been made for other phenotypes. 5 In this context, it is noteworthy that LOY also coexists with mutations causing clonal hematopoiesis of indeterminate potential, 3 which was recently reported to be more prevalent in young cryptogenic stroke compared with controls.…”

“…We analyzed associations between LOY and outcome by binary logistic regression analyses. As covariates, we selected age and diabetes because they are associated with both LOY and ischemic stroke outcome 3 , 6 , 10 and the National Institutes of Health Stroke Scale as it is a strong predictor of poststroke outcome. 10 Separate models for each covariate were used to minimize data missingness.…”

“… 1 , 2 We found that a polygenic risk score for LOY 5 is associated with poor poststroke outcome. 6 Based on this background, we hypothesized that LOY itself is associated to poor ischemic stroke outcome.…”

Genetics of ischemic stroke functional outcome

“…Traditionally considered a marker of aging, mLOY has recently been linked to various pathologies including cancer, Alzheimer’s disease, and cardiovascular disease [ 109 ]. Recently, an mLOY polygenic risk score was associated with worse ISFO (3-month mRS) [ 137 ] (Fig. 5 ).…”