Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.

TitleExome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.
Publication TypeJournal Article
Year of Publication2022
AuthorsXu, H, Nguyen, K, Gaynor, BJ, Ling, H, Zhao, W, McArdle, PF, O'Connor, TD, O Stine, C, Ryan, KA, Lynch, M, Smith, JA, Faul, J, Hu, Y, Haessler, JW, Fornage, M, Kooperberg, C, Perry, JA, Hong, CC, Cole, JW, Pugh, E, Doheny, K, Kardia, SLR, Weir, DR, Kittner, SJ, Mitchell, BD
Corporate AuthorsSiGN Consortium
ISSN Number2073-4425
KeywordsExome, Gene Frequency, Genome-Wide Association Study, Ischemic stroke, Stroke

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., < 4.7 × 10), including two common SNPs in 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 ( = 5613 cases) or UK Biobank ( = 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.

Citation Key13496
PubMed ID36672803
PubMed Central IDPMC9858999
Grant ListMC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 NS114045 / NS / NINDS NIH HHS / United States
P30 AG028747 / AG / NIA NIH HHS / United States
R01 NS105150 / NS / NINDS NIH HHS / United States
R01 NS100178 / NS / NINDS NIH HHS / United States
R01 HL135129 / HL / NHLBI NIH HHS / United States