Fig. 1

Roadmap for studying genetic variants associated with epigenetic age acceleration in blood. The roadmap depicts our analytical procedures. a The study sets were divided into two stages according to European (EUR) and non-European ancestry. b Stage 1 yielded GWAS summary data on all QC SNPs and the combined stage yielded GWAS summary data on the SNPs with Meta EUR P < 1.0 × 10⁻⁵ at stage 1. Genome-wide significant loci were determined based on the association results from the combined stage. c Describes our transcriptomic studies: (I) blood cis-eQTL to identify potential functional genes, (II) summary statistics based Mendelian randomization (SMR) to assess the causal associations between expression levels and IEAA (or EEAA). d Describes our detailed analysis in the TERT locus, which was implicated by our GWAS of IEAA. Bidirectional Mendelian randomization via MR-Egger analysis did not reveal a direct causal effect between leukocyte telomere length and IEAA. Our in vitro studies validate our genetic findings by demonstrating that hTERT over-expression promotes epigenetic aging in e. To explore molecular pathways underlying epigenetic age acceleration, we conducted gene set enrichment analysis, as listed in f. Finally, we performed LDSC genetic correlation between IEAA or EEAA and a broad category of complex traits, followed by MR-Egger regression analysis, as depicted in g. Abbreviations: GE = gene expression, LTL = leukocyte telomere length