• The copy number variation and stroke (CaNVAS) risk and outcome study

      Cole, John W.; Adigun, Taiwo; Akinyemi, Rufus; Akpa, Onoja Matthew; Bell, Steven; Chen, Bowang; Jimenez Conde, Jordi; Lazcano Dobao, Uxue; Fernandez, Israel; Fornage, Myriam; et al. (Public Library of Science, 2021-04-19)
      Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.
    • Effects of the BDNF Val66Met polymorphism on functional status and disability in young stroke patients

      Braun, R.G.; Kittner, S.J.; Ryan, K.A.; Cole, J.W. (Public Library of Science, 2020-12-11)
      Background and purpose The preponderance of evidence from recent studies in human subjects supports a negative effect of the BDNF Val66Met polymorphism on motor outcomes and motor recovery. However prior studies have generally reported the effect of the Met allele in older stroke patients, while potential effects in younger stroke patients have remained essentially unexamined. The lack of research in younger patients is significant since aging effects on CNS repair and functional recovery after stroke are known to interact with the effects of genetic polymorphisms. Here we present a study of first-ever ischemic stroke patients aged 15–49 years that examines the effect of Met carrier status on functional disability. Methods 829 patients with a first ischemic stroke (Average age = 41.4 years, SD = 6.9) were recruited from the Baltimore-Washington region. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Our sample contained 165 Met carriers and 664 non-Met carriers. Modified Rankin scores as recorded at discharge were obtained from the hospital records by study personnel blinded to genotype, and binarized into “Good” versus “Poor” outcomes (mRS 0–2 vs. 3+), with mRS scores 3+ reflecting a degree of disability that causes loss of independence. Results Our analysis showed that the Met allele conveyed a proportionally greater risk for poor outcomes and disability-related loss of independence with mRS scores 3+ (adjusted OR 1.73, 95% CI 1.13–2.64, p = 0.01). Conclusions The BDNF Val66Met polymorphism was negatively associated with functional outcomes at discharge in our sample of 829 young stroke patients. This finding stands in contrast to what would be predicted under the tenets of the resource modulation hypothesis (i.e. that younger patients would be spared from the negative effect of the Met allele on recovery since it is posited to arise as a manifestation of age-related decline in physiologic resources). This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
    • Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke

      Johansson, Malin; Pedersen, Annie; Cole, John W; Lagging, Cecilia; Lindgren, Arne; Maguire, Jane M; Rost, Natalia S; Söderholm, Martin; Worrall, Bradford B; Stanne, Tara M; et al. (Wolters Kluwer Health, 2021-11-12)
      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.