White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.