Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Bibliographical noteFunding Information:
REM, SH, and AL are supported by a National Institute of Health U01 grant, U01AG060908–01. REM and DLM are supported by Alzheimer’s Research UK major project grant, ARUK-PG2017B-10. RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol. CR and RCR receive support from a Cancer Research UK Program Grant (C18281/A191169). CLR, JLM, and RCR are members of the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5). IJD is supported by Age UK (Disconnected Mind program), UKRI Medical Research Council grant, MR/R0245065/1, and by National Institute of Health R01 grant, 1R01AG054628-01A1. GD is supported by the University of Edinburgh School of Philosophy, Psychology and Language Sciences. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Cohort-specific acknowledgements are presented in Additional file .
© 2021, The Author(s).