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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.

Original publication

DOI

10.1038/s41467-020-19111-2

Type

Journal article

Journal

Nature communications

Publication Date

08/12/2020

Volume

11

Addresses

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, 33000, Bordeaux, France.

Keywords

International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC)