Cerebral small vessel disease genomics and its implications across the lifespan

Nat Commun. 2020 Dec 8;11(1):6285. doi: 10.1038/s41467-020-19111-2.

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.

Publication types

  • Meta-Analysis
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Cerebral Small Vessel Diseases / complications
  • Cerebral Small Vessel Diseases / diagnosis
  • Cerebral Small Vessel Diseases / genetics*
  • Diffusion Tensor Imaging
  • Female
  • Genetic Loci
  • Genome-Wide Association Study
  • Humans
  • Hypertension / epidemiology
  • Hypertension / genetics*
  • Male
  • Medical History Taking
  • Mendelian Randomization Analysis
  • Middle Aged
  • Risk Assessment
  • Risk Factors
  • Stroke / epidemiology
  • Stroke / genetics*
  • White Matter / diagnostic imaging
  • Young Adult

Grant support