RT Journal Article
SR Electronic
T1 Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e634
DO 10.1212/NXG.0000000000000634
VO 7
IS 6
A1 Johansson, Malin
A1 Pedersen, Annie
A1 Cole, John W.
A1 Lagging, Cecilia
A1 Lindgren, Arne
A1 Maguire, Jane M.
A1 Rost, Natalia S.
A1 Söderholm, Martin
A1 Worrall, Bradford B.
A1 Stanne, Tara M.
A1 Jern, Christina
YR 2021
UL http://ng.neurology.org/content/7/6/e634.abstract
AB Background and Objectives To 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.Methods We 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.Results Increasing 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.Discussion In 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.CH=clonal hematopoiesis; CI=confidence interval; GISCOME=Genetics of Ischemic Stroke Functional Outcome; GWAS=genome-wide association study; mCA=mosaic chromosomal alteration; mLOY=mosaic loss of chromosome Y; mRS=modified Rankin Scale; OR=odds ratio; PRS=polygenic risk score