Abstract
DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10−11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
Highlights
We performed LD-based clumping procedure in PLINK with a threshold of r2 set at 0.1 in a window size of 250 kb to yield the leading variants present in both GWAS summary data sets, as needed. For those traits showing significant causal effects on IEAA, we performed a sensitivity analysis to check if the significant associations spuriously resulted from the instrumental variables (SNPs) co-locating (±1 Mb) with CpG sites from the DNAm age estimators
For those traits showing significant causal effects on IEAA (or EEAA), we performed a sensitivity analysis (stratified analysis) to check if the significant associations spuriously resulted from the instrumental variables (SNPs) co-locating (±1 Mb) with CpG sites from the DNAm age estimators
Summary
For IEAA, we identified 264 associated variants, mapping to five genomic loci (3q25.33, 5p15.33, 6p22.3, 6p22.2, and 17q22, Table 1, Supplementary Data 1, Fig. 2, and Supplementary Fig. 2). 6p22.2 and 6p22.3, colocate (within 1 Mb) with CpGs that contribute to the Horvath estimate of DNAm age (Table 1 and Supplementary Data 1), and it is possible that these genotypic associations with IEAA arise from direct SNP effects on local methylation To learn about potential functional consequences of these associations, we conducted cis-eQTL analysis for each locus associated with IEAA or EEAA, using data on leukocyte mRNA expression in up to 15,295 samples from five studies (Fig. 1c; Methods section). Each putative cis-eQTL was analyzed by summary data-based Mendelian randomization
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