Genes (Dec 2022)

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

  • Huichun Xu,
  • Kevin Nguyen,
  • Brady J. Gaynor,
  • Hua Ling,
  • Wei Zhao,
  • Patrick F. McArdle,
  • Timothy D. O’Connor,
  • O. Colin Stine,
  • Kathleen A. Ryan,
  • Megan Lynch,
  • Jennifer A. Smith,
  • Jessica D. Faul,
  • Yao Hu,
  • Jeffrey W. Haessler,
  • Myriam Fornage,
  • Charles Kooperberg,
  • on behalf of the Trans-Omics for Precision Medicine (TOPMed) Stroke Working Group,
  • James A. Perry,
  • Charles C. Hong,
  • John W. Cole,
  • Elizabeth Pugh,
  • Kimberly Doheny,
  • Sharon L. R. Kardia,
  • David R. Weir,
  • Steven J. Kittner,
  • Braxton D. Mitchell

DOI
https://doi.org/10.3390/genes14010061
Journal volume & issue
Vol. 14, no. 1
p. 61

Abstract

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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 −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 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.

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