Mapping Cell-Type-Specific Regulatory Variants in Vascular Dementia by Integrating Single-Cell Chromatin...

Vascular dementia (VaD), the second most common form of dementia, is a growing burden in aging populations and lacks disease-modifying therapy. Although immunerelated regulatory mechanisms are increasingly implicated, the role of immune cell-specific chromatin accessibility variants remains poorly understood.

Using 379 instruments across 377 chromatin accessibility peaks in 17 immune cell types, we performed Mendelian randomization against FinnGen GWAS data, with independent evaluation in the UK Biobank. Because most loci were instrumented by a single variant, formal heterogeneity and horizontal-pleiotropy testing was not feasible. Candidate effector genes were then investigated by regulatory annotation and Bayesian colocalization of single-cell eQTLs with the VaD GWAS.

Four loci reached FDR < 0.05:a risk-increasing B cell/naïve B cell enhancer at chr7:24758459-24759192 (OR = 2.78 and 2.29) and the protective NK/cytotoxic NK cell loci at chr8:20109125-20109944 (OR = 0.63 and 0.62). In the UK Biobank, the B cell association was directionally concordant but, given the few cases, is supportive rather than confirmatory. Regulatory annotation and colocalization nominated GSDME as a candidate effector gene, with moderate evidence in immature B cells.

These findings are consistent with peripheral immune regulation at cell type-specific regulatory elements; brain-resident populations were not examined. The nomination of GSDME generates the hypothesis of a B cell pyroptosis-related mechanism; this is an association-level, hypothesis- generating result rather than evidence of a causal or mediating role, and remains to be validated.

Immune cell-type-specific chromatin accessibility variation-notably a B cell locus nominating GSDME as a candidate effector gene, alongside a protective NK signal-is associated with VaD risk, generating cell-resolved hypotheses. As most instruments were single variants, these results should be read as genetic associations rather than causal inference.