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

Abstract

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.

A novel scatterplot-based method to detect copy number variation (CNV)

“…We nevertheless observed heterogeneity across the analyzed CNV regions with the majority of the false-positive PennCNV findings occurring in a single region. Since this clearly gives our current work the character of a pilot study, we are planning a follow-up study to analyze a larger set of syndromic CNVs (Wang et al, 2007) in samples from the CaNVAS study (Cole et al, 2021), genotyped on different platforms.…”

“…Illumina 2.5 M SNP data from 13,245 individuals from the Health and Retirement study (Aschwanden et al, 2019), genotyped at the Center of Inherited Disease Research (CIDR) of the Johns Hopkins University School of Medicine, Baltimore, United States, were used for analysis. The study population is part of the Copy Number Variation and Stroke (CaNVAS) study (Cole et al, 2021). CNV analysis was also performed in all samples using the PennCNV software as described before (Wang et al, 2007;Grond-Ginsbach et al, 2017).…”

Genetics of ischemic stroke functional outcome

“…CNV of dose-sensitive genes independently contributed to unfavorable outcomes in IS patients (3-month mRS) [ 215 ]. Future studies aim to further elucidate the impact of CNV on stroke risk and outcome [ 62 ]. Mosaic loss of chromosome Y (mLOY) is an insidious progression of aneuploidy in somatic cells.…”