Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke.

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Rutten-Jacobs, Loes CA 
Thijs, Vincent 
Holliday, Elizabeth G 
Levi, Chris 

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. METHODS: We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. RESULTS: The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. CONCLUSIONS: Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

cerebral small vessel diseases, genetic association studies, genetics, leukoencephalopathies, stroke, lacunar, Adult, Aged, Aged, 80 and over, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Registries, Risk, Stroke, Lacunar
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Ovid Technologies (Wolters Kluwer Health)
Hugh Markus is supported by an NIHR Senior Investigator award. Hugh Markus and Steve Bevan are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. Collection of the UK Young Lacunar Stroke Resource was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping and MT were supported by a project grant from the Stroke Association (TSA 2013/01). The research was also supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Vincent Thijs is supported by a Flemish Fund of Scientific Research (FWO) Clinical Investigator Grant