Faculty, Staff and Student Publications
Publication Date
12-24-2022
Journal
Genes
Abstract
Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.
Keywords
Humans, Genome-Wide Association Study, Ischemic Stroke, Exome, Gene Frequency, Stroke, African American, exome wide association study, exome array, ischemic stroke, rare coding variants
DOI
10.3390/genes14010061
PMID
36672803
PMCID
PMC9858999
PubMedCentral® Posted Date
12-24-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Genetics Commons, Genomics Commons, Medical Genetics Commons, Medicine and Health Commons, Public Health Commons, Race and Ethnicity Commons