Common mitochondrial sequence variants in ischemic stroke

Abstract

Objective: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV).

Methods: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke.

Results: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037).

Interpretation: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.

Figure 1. Flowchart of genetic score-based analysis pipeline

Boxes represent the steps for generation and application of the genetic score to test associations with ischemic stroke. Hexagons represent the locations where permutation algorithms can be applied to test the score generated against the null-hypothesis. OR = Odds Ratio, SNP = Single Nucleotide Polymorphism.

Figure 2. Forest plot of meta-analysis of association between mitochondrial genetic score and ischemic stroke

GCNKSS = Greater Cincinnati Northern Kentucky Stroke Study, Het p-value = heterogeneity p-value, I² = % of effect size attributable to meta-analysis heterogeneity, ISGS/SWISS = Ischemic Stroke Genetic Study/Siblings with Ischemic Stroke Study, JUSS = Jagiellonian University Stroke Study, MGH = Massachusetts General Hospital Ischemic Stroke Genome-wide Association Study