Abstract
BACKGROUND: Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function. RESULTS: Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR. CONCLUSION: This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.