Genetic Evidence Supports a Potential Role of WTAP-related m6A Regulation in Vascular Dementia: Insights from...

Vascular dementia (VAD) is a major cause of cognitive decline, yet its molecular determinants remain incompletely understood. Emerging evidence suggests that N6-methyladenosine (m6A) RNA modification may influence cerebrovascular biology; however, its potential causal relevance to VAD has not been systematically evaluated in human genetic studies. We conducted Mendelian randomization (MR) using m6A-related expression quantitative trait loci (eQTLs) as instrumental variables and FinnGen VAD GWAS data as the outcome. Significant signals were further examined using summary-data-based Mendelian randomization (SMR) and differential expression analysis of GSE122063. For the bulk transcriptome dataset (GSE122063), samples were treated as independent observations based on dataset structure (no repeated multi-region sampling per subject), and linear modeling was performed using standard normalization procedures. Mediation by 473 gut microbial taxa was evaluated using two-step MR. Weighted gene co-expression network analysis (WGCNA), single-cell RNA sequencing (GSE282111), and phenome-wide association studies (PheWAS) were applied to explore co-expression patterns, cellular distribution, and phenotypic associations. Across MR models, genetically predicted WTAP expression was associated with increased VAD risk (IVW OR = 1.28, 95% CI: 1.14-1.45, P = 4.9 × 10⁻⁵). SMR analysis provided supportive evidence for this association (OR = 1.26, P = 0.0126), and GEO data indicated higher WTAP expression in VAD brain tissue. Mediation analysis suggested partial indirect effects through gut microbial taxa, including Halomonadaceae (38.8%) and Bacillus velezensis (19.0%). WGCNA identified a VAD-related blue module (cor = 0.45, P = 3 × 10⁻⁵), enriched in the Apelin signaling pathway. Single-cell analysis showed cell-type-specific WTAP expression patterns, particularly in vascular smooth muscle cells and neurons. PheWAS revealed associations with neurological, inflammatory, and lipoprotein(a)-related traits. This integrative genetic and transcriptomic analysis provides convergent evidence supporting a potential role of WTAP in VAD susceptibility and suggests links between m6A regulation, gut microbiota, and cerebrovascular biology. These findings generate testable hypotheses for future experimental studies but require functional validation to confirm underlying mechanisms.