Cerebral small vessel disease genomics and its implications across the lifespan

International Headache Genetics Consortium, Lannie Ligthart, Dorret Boomsma, Jouke Jan Hottenga

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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 languageEnglish
Article number6285
Pages (from-to)1-18
Number of pages18
JournalNature Communications
Volume11
DOIs
Publication statusE-pub ahead of print - 8 Dec 2020

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