Genetic evidence links hypertension to accelerated brain aging.

Hypertension affects one-third of adults and is a major comorbidity of neurocognitive disorders. The causal relationship, shared genetic architecture, and upstream mechanisms linking hypertension to brain aging remain unclear. Hypertension GWAS datasets from MVP and FinnGen R12 were meta-analyzed as the exposure, and a European-ancestry brain age gap (BAG) GWAS derived from the UK Biobank and LIFE-Adult cohorts was used as the outcome. MR and GSMR assessed causality. LDSC, HDL, and S-LDSC estimated genetic correlation. Four TWAS methods (MAGMA, FUSION, JTI-PrediXcan, FOCUS) mapped associations to genes, followed by SMR for causal validation and PoPS for prioritization. GSMAP with spatial transcriptomics characterized regional and cell-type enrichment. Hypertension and brain aging were genetically correlated, and MR and GSMR analyses suggested a causal effect of hypertension on increased brain age gap. TWAS identified 15 shared Hypertension-BAG genes, 10 supported by SMR. PoPS prioritized TRIM47 as the core gene. Shared signals were enriched in meninges, fiber tracts, cortical layer 1, and CA1 stratum lacunosum/radiatum, with cell-type enrichment in meninges, smooth muscle cells, oligodendrocytes, and astrocyte subtypes. Hypertension is genetically correlated with, and shows evidence of a causal effect on, accelerated brain aging. TRIM47 is a core gene bridging hypertension and BAG. GSMAP-based spatial enrichment provides a hypothesis-generating framework for understanding vascular, meningeal, and myelin-related pathways linking hypertension to increased brain age gap.