Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

Abstract

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

The MIND diet, brain transcriptomic alterations, and dementia

“…Genes showing the strongest positive associations with MIND diet included TCIM and MPO, which have been related to educational attainment, and cognitive performance in depression in previous GWAS. 43,44 Genes showing the strongest negative associations included CC2D2B, PDXDC2P, and MBIP, which are linked to AD, brain structure (e.g., white matter hyperintensities), and educational attainment; 43,[45][46][47] and INPP5B and IGSF5, which have been related to cardiovascular outcomes 48,49 in prior genetic studies (Figure 2, Supplementary Table S1). In sensitivity analyses, associations between MIND diet score and the 50 genes did not materially change after further adjusting for estimated cell type proportions, other lifestyle factors, or excluding individuals classified with dementia at baseline (Supplementary Figure S2).…”