Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Genome Biol. 2021 Jun 29;22(1):194. doi: 10.1186/s13059-021-02398-9.


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.

Keywords: DNA methylation; Epigenetic clock; GWAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / genetics
  • Adiposity / immunology
  • Aging / genetics*
  • Aging / immunology
  • Biomarkers / metabolism
  • C-Reactive Protein / genetics
  • C-Reactive Protein / immunology
  • CpG Islands
  • DNA Methylation*
  • Educational Status
  • Epigenesis, Genetic*
  • Genetic Loci*
  • Genetic Markers
  • Genome, Human
  • Genome-Wide Association Study
  • Granulocytes / cytology
  • Granulocytes / immunology
  • Humans
  • Immunity, Innate
  • Lipid Metabolism / genetics
  • Lipid Metabolism / immunology
  • Multifactorial Inheritance*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / immunology


  • Biomarkers
  • Genetic Markers
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • C-Reactive Protein