Genetic influence of the brain on epigenetic age acceleration: evidence of a large-scale genetic correlation study

The relationship between the brain and aging remains unclear. Our objective is to explore the causal connections between brain structure,gene expression, and traits associated with aging. Mendelian randomization(MR) analysis was conducted to explore the associations between brain structures and aging-related traits including GrimAge acceleration(GrimAA), PhenoAge acceleration (PhenoAA), HannumAge acceleration(HannumAA), HorvathAge acceleration(HorvathAA), and leukocyte telomere length(LTL). The Linkage Disequilibrium Score Regression(LDSC) method was employed to identify the shared genetic etiology between brain structures and aging. The Summary Data-based Mendelian Randomization(SMR) was utilized to investigate which brain genes have a causal influence on aging. We also examined the expression of the 8 genes derived from the SMR analysis across different cell types in post-mortem human brain specimens. The phenotypes potentially linked to genetics, as indicated by the LDSC outcomes, are as follows:148 phenotypes with GrimAA,150 phenotypes with HannumAA, 160 phenotypes with HorvathAA, 160 phenotypes with PhenoAA,and 110 phenotypes with LTL. Concerning the causal link between brain structures and aging-related traits, 7 brain structures consistently demonstrated a causative effect on GrimAA, while 29 brain structures exerted a causal influence on PhenoAA.Additionally, 7 BIDs revealed a causal relationship with HannumAA. There are 10 and 14 brain structures have a causative effect on HorvathAA and LTL, respectively. SMR revealed that 8 genes(CCDC144B, SHMT1, FAM106A, FAIM, CTD-2303H24.2, EBAG9P1, USP32P2 and OGFOD3) expression in different brain regions affected aging. These genes exhibit different expression patterns in various cells. Our results are in line with the possibility of a causal connection between aging and brain structure.