Fig. 7: Biological pathways and functional gene sets enriched in age-related CpG sites.

Selected results from (1) genomic region-based GREAT functional enrichment (top), (2) gene-based EWAS–TWAS enrichment analysis (middle) and (3) genomic region-based EWAS–GWAS enrichment analysis (bottom). All enrichment analyses were based on hypergeometric tests with background based on the mammalian array. The bar plots in the first column report the total number of genes at each studied gene set adjusted based on the background. The left and right parts of the x axis list the top 1,000 CpG sites that increased or decreased with age from meta-EWAS of age across all blood, skin, liver, muscle, brain and cerebral cortex tissues, respectively. On the right side, the first column color band depicts the three types of enrichment analyses. The second column color band depicts (1) six ontologies in the GREAT analysis, (2) four species in our TWAS collections and (3) seven categories of human complex traits in the GWAS as described in the legend. The heatmap color codes −log₁₀ (hypergeometric P values). Unadjusted hypergeometric P values (number of overlapped genes) are reported in the heatmap provided (1) false discovery rate < 0.05, P < 0.001 and the number of overlapped genes ≥3 for GREAT analysis, (2) P < 0.05 for EWAS–TWAS and (3) P < 0.05 for EWAS–GWAS. Comprehensive results can be found in Supplementary Data 10, 12 and 13. Abbreviations: act., activity; deg., degeneration; AgeAccelGrim, epigenetic age acceleration derived from the mortality clock: GrimAge²³; DNAmGran, DNAm granulocyte (Supplementary Note 5); GIANT, Genetic Investigation of ANthropometric Traits; GTEx, Genotype–Tissue Expression; HD, Huntington’s disease; hipp., hippocampal; LTL, leukocyte telomere length; MSigDB, Molecular Signatures Database; mus., muscle; OPCs, oligodendrocyte precursor cells; reg., regulation; TACs, transiently amplifying progenitor cells; WHR, waist-to-hip ratio.