Genomics of diffusion-imaging integrating GWAS, exome data and single-cell sequencing unravels lifespan determinants of cerebral small vessel disease
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Peak width of skeletonized mean diffusivity (PSMD) is an emerging automated diffusion imaging marker showing clinically relevant changes in cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no mechanism-based treatment. We conducted a genome-wide association study of PSMD in 58,403 participants from 24 population-based cohorts (89% European, 10% East-Asian, 1% African-American), identifying 31 independent common variant associations. Additionally, a whole-exome sequencing analysis in 32,957 participants yielded associations of PSMD with single and burden of rare coding variants in four novel genes. Mendelian randomization supported causal association of higher blood pressure with larger PSMD values, and of larger PSMD with an increased risk of stroke, especially intracerebral hemorrhage. Strikingly, genetic susceptibility to white matter hyperintensities, an established MRI-marker of cSVD, was associated with higher PSMD from early childhood to older age, with prominent lifespan effects for VCAN and SMG6 . Leveraging unique brain single-cell sequencing resources we showed temporal changes in the cell-type specificity of these genes in the developing brain and overall enrichment of PSMD risk loci in genes expressed in fetal brain endothelial cells. Finally, through extensive integration with multi-omics resources, we provide precious leads for gene prioritization to accelerate drug discovery for cSVD.
