A genome-wide association study identifies Asian-specific genetic susceptibility for epigenetic age acceleration

Genome-wide association studies (GWASs) have been performed on multiple epigenetic clocks to understand the genetic underpinnings of epigenetic age acceleration (EAA). To explore ethnic differences and individual variability in Asian populations, we conducted a GWAS of EAA using multiple epigenetic clocks in the Korean population. Genome-wide single-nucleotide polymorphism (SNP) and methylation data were obtained from 1962 Korean individuals. Five epigenetic clocks (Hannum, DNAm PhenoAge, GrimAge, Zhang2019, and Horvath-Skin&Blood) were considered. GWASs, as well as gene-based, pathway enrichment, quantitative real-time polymerase chain reaction, and quantitative trait loci analyses, were performed to investigate the biological mechanisms. Pleiotropy analyses and drug repurposing were used to explore clinical implications. Six SNPs were independently associated with EAAs (P < 5 × 10^-8). The DNAm PhenoAge-EAA was associated with ASPA and SPATA22 (P < 2.66 × 10^-6), involved in Canavan disease and apoptosis, and the Zhang2019 was associated with ENO2, GNB3, USP5, TPI1, and CDCA3 (P < 2.66 × 10^-6), which are implicated in monosaccharide catabolism. Particularly, the expression levels of SPATA22, ENO2, USP5, and TPI1 increased in senescent cells. EAA-associated genes showed strong affinities with GW0742, a peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist. In addition, the Zhang2019-EAA-associated SNP showed pleiotropy in liver function biomarkers, including iron and bilirubin. We identified six Asian-specific EAA-associated genetic variants, including five novel SNPs. The novel SNPs, which are rare in European populations, could implicate ancestry-related genetic differences in epigenetic aging. Furthermore, the genetic implications of the DNAm PhenoAge-EAA and Zhang2019-EAA on apoptosis and liver function may contribute to a better understanding of EAA in East Asian populations.