Exome array analysis of ischaemic stroke: results from a southern Swedish study

Area of Science:

• Genetics
• Neurology
• Cardiovascular Disease

Background:

• Genome-wide association studies (GWAS) have identified limited risk loci for ischaemic stroke.
• Existing variants explain a small fraction of the genetic contribution to ischaemic stroke.
• Coding variants, such as those causing amino acid substitutions or premature protein termination, may significantly impact disease risk.

Purpose of the Study:

• To perform an exome array analysis to identify genetic variants associated with ischaemic stroke risk.
• To investigate the role of exome variants in the genetic etiology of ischaemic stroke.

Main Methods:

• Exome genotyping of 2385 ischaemic stroke patients and 6077 controls using the Illumina HumanOmniExpressExome BeadChip.
• Single-variant and gene-based association analyses were conducted for exome variants with a minor allele frequency < 5%.
• A parallel GWAS was performed using 700,000 common markers with imputation.

Main Results:

• No single exome variant or gene reached statistical significance for association with overall ischaemic stroke after Bonferroni correction.
• The strongest single-variant association was a missense variant in DNAH11 (rs143362381; P = 5.01 × 10^-6).
• Previously reported associations for PITX2 and ZFHX3 with cardioembolic stroke were replicated.

Conclusions:

• The exome array analysis did not identify novel significant associations for ischaemic stroke.
• Larger, well-defined, and subtyped patient cohorts are required for future exome variant studies.
• The genetic architecture of ischaemic stroke likely involves complex interactions and potentially rare variants not detected in this study.