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.
Highlights
In the European-only SNP-main-effects analysis, 22 independent loci harbored common variants associated with White matter hyperintensities (WMH) volume at genome-wide significance (P < 5 × 10−8, Table 1, Fig. 2), lead SNPs for each independent locus were confirmed by both linkage disequilibrium (LD) clumping and GCTA-COJO24
Among the 39 WMH eGenes with high colocalization probability (Fig. 5, Supplementary Data 21), 4 (MAPT, CRHR1, CALCRL, NOTCH4) are registered as targets of approved drugs in the DrugBank database and the Therapeutic Target Database (Supplementary Data 22). This largest genetic study to date on complex SVD13,14,16–18, leveraging genetic and brain-imaging information from 50,970 older community persons, triples the number of genetic loci associated with cerebral small vessel disease (SVD) and shows that this genetic risk results in detectable brain changes among asymptomatic young adults in their twenties
We further demonstrate the importance of higher blood pressure (BP) as a risk factor for WMH even below clinical thresholds for HTN
Summary
We examined whether genetically predicted larger WMH volume was associated with increased risk of stroke and Alzheimertype dementia, the most common age-related neurological diseases, and with lower cognitive performance in older age, using previously reported GWAS data (Supplementary Table 2). Using two-sample MR, which implements the inverse-variance weighting (IVW) method, we observed evidence for significant causal associations after Bonferroni correction for multiple testing (P < 3.6 × 10−3) between WMH volume and increased risk of Alzheimer-type dementia, with no statistical evidence of horizontal pleiotropy using Cochran’s Q statistic (Q-PHet≥0.01, Fig. 4, Supplementary Data 16).
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