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

Area of Science:

• Genetics
• Neurology
• Epidemiology

Background:

• Genome-wide association studies (GWAS) have identified common genetic variants linked to ischemic stroke, predominantly in non-coding DNA regions.
• The role of rare coding variants in ischemic stroke etiology remains less understood due to their low frequency.

Purpose of the Study:

• To evaluate the contribution of rare coding genetic variants to ischemic stroke risk.
• To identify novel genetic associations for ischemic stroke beyond common variants.

Main Methods:

• Exome array analysis was performed on 9,721 ischemic stroke cases and 12,345 controls, examining 106,101 single nucleotide polymorphisms (SNPs).
• Statistical association testing was conducted at an array-wide significance threshold (p < 4.7 × 10^-7).
• Replication analysis was attempted in independent cohorts (TOPMed Stroke and UK Biobank).

Main Results:

• Fifteen coding variants showed significant association with ischemic stroke, including two common variants in the ABO gene.
• Thirteen of these variants were extremely rare (minor allele frequency < 0.1%) in European Caucasians, with associations primarily driven by African American samples.
• Replication of these rare variant associations was not observed in TOPMed Stroke or UK Biobank cohorts, likely due to low power and limited diversity.

Conclusions:

• The study underscores the challenges in identifying rare variant associations for ischemic stroke using current array-based genotyping technologies.
• Acquiring large, genetically diverse, and well-powered cohorts is crucial for the robust investigation of rare genetic variants in ischemic stroke.