Background: Genome-wide association (GWA) studies have identified a few risk loci for ischemic stroke. Yet, these variants can explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis of rare coding variants for ischemic stroke.
Methods: Patients with ischemic stroke (n=2,385) and control subjects (n=6,077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis was performed of non-synonymous variants with minor allele frequency <5% (n=33,130). A separate genome-wide association (GWA) analysis was also performed, based on 700,000 genotyped common markers and subsequent imputation according to 1000 Genomes.
Results: No variant in the exome analysis was significantly associated with ischemic stroke after Bonferroni correction (all p>1.5x10-6). The two strongest associations were found for missense variants in the genes DNAH11 (odds ratio: 0.14 [95% confidence interval: 0.05-0.41], p=2.9x10-4), and ATF6 (odds ratio: 2.03 [1.38-2.98], p=3.6x10-4). The GWA analysis showed that the sample was homogenous (median genomic inflation factor=1.006). No genome-wide significant association with overall ischemic stroke risk was found (all p>5x10-8). However, previously reported associations for the PITX2 and ZFHX3 gene loci with the subtype cardioembolic stroke were replicated (p=7x10-15 and 6x10-3).
Conclusion: None of the coding non-synonymous genetic variants reached the pre-defined significance level in this exome array analysis for ischemic stroke. Further studies on exome variation should be performed in even larger samples to identify novel genetic risk factors.