White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Background and Purpose - The presence of subclinical vascular brain disease, including white matter lesions and lacunar infarcts, substantially increases the risk of clinical stroke. White matter microstructural integrity is considered an earlier, potentially better, marker of the total burden of vascular brain disease. Its association with risk of stroke, a focal event, remains unknown. Methods - From the population-based Rotterdam Study, 4259 stroke-free participants (mean age: 63.6 years, 55.6% women) underwent brain magnetic resonance imaging, including diffusion magnetic resonance imaging, between 2006 and 2011. All participants were followed up for incident stroke until 2013. Cox proportional hazards models were used to associate markers of the microstructure of normal-appearing white matter with risk of stroke, adjusting for age, sex, white matter lesion volume, lacunar infarcts, and additionally for cardiovascular risk factors. Finally, we assessed the predictive value of white matter microstructural integrity for stroke beyond the Framingham Stroke Risk Profile. Results - During 18 476 person-years of follow-up, 58 people experienced a stroke. Both lower fractional anisotropy and higher MD increased risk of stroke, independent of age, sex, cardiovascular risk factors, white matter lesion volume, and lacunar infarcts (hazard ratio per SD increase in: fractional anisotropy: 0.75 [95% confidence interval, 0.57-0.98] and MD: 1.50 [95% confidence interval, 1.08-2.09]). MD improved stroke prediction beyond the Framingham Stroke Risk Profile (continuous net reclassification improvement: 0.52 [95% confidence interval, 0.24-0.81]). Conclusions - Future stroke is predicted not only by prevalent vascular lesions but also by subtle alterations in the microstructure of normal-appearing white matter. Inclusion of this effect in risk prediction models produces a significant advantage in stroke prediction compared with the existing Framingham Stroke Risk Profile.