Genetic contribution to white matter hyperintensity burden in early- and late-onset ischemic stroke patients

Abstract

White matter hyperintensity volume (WMHV) is associated with greater risk of ischemic stroke, and discovery of genetic markers of increased WMHV may contribute to improved stroke risk prediction models, leading to novel stroke prevention strategies, especially in high-risk individuals. These genetic markers may have a greater effect in early-onset stroke patients due to their shorter exposure to environmental factors, or play a protective role in late-onset stroke patients. In a genome-wide study designed to discover single nucleotide polymorphisms (SNPs) associated with white matter hyperintensity burden in early- and late-onset stroke patients, approximately nine million SNPs were ascertained in 781 subjects, whose age, sex, WMHV, and history of hypertension, hyperlipidemia, and tobacco use were also determined. Association analyses in three subpopulations (patients with early-onset stroke, patients with average age of stroke onset, and patients with late-onset stroke) provided lists of SNPs associated with WMHV, and these SNPs were used to calculate genetic risk (GR) scores for each subject. Single-variable linear regression was used to identify which of the baseline characteristics were nominally significant, for inclusion in multivariable regression models with and without the effect contributed by the GR scores. We found that GR scores calculated using SNPs discovered in patients with early-onset stroke significantly predicted of white matter burden in patients with average age of stroke onset, and that GR scores calculated with a panel of SNPs discovered in patients with average age of stroke onset predicted WMHV in patients with late-onset stroke. Furthermore, our findings suggest a different genetic mechanism for increased WMHV in early-onset stroke patients.