@article{18754,
  abstract     = {Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort. We observed a maximum of 12,033 significant findings (p < 3.6 × 10−8) for BMI in a marginal linear regression EWAS. By contrast, a joint and conditional Bayesian penalized regression approach yielded 27 high-confidence associations with BMI. EpiScores trained in GS performed well in both Scottish and Singaporean test cohorts (Lothian Birth Cohort 1936 [LBC1936] and Health for Life in Singapore [HELIOS]). The EpiScores for BMI and total cholesterol performed best in HELIOS, explaining 20.8% and 7.1% of the variance in the measured traits, respectively. The corresponding results in LBC1936 were 14.4% and 3.2%, respectively. Differences were observed in HELIOS for body fat, where the EpiScore explained ∼9% of the variance in Chinese and Malay -subgroups but ∼3% in the Indian subgroup. The EpiScores also correlated with cognitive function in LBC1936 (standardized βrange: 0.08–0.12, false discovery rate p [pFDR] < 0.05). Accounting for the correlation structure across the methylome can vastly affect the number of lead findings in EWASs. The EpiScores of metabolic traits are broadly applicable across populations and can reflect differences in cognition.},
  author       = {Smith, Hannah M. and Ng, Hong Kiat and Moodie, Joanna E. and Gadd, Danni A. and Mccartney, Daniel L. and Bernabeu, Elena and Campbell, Archie and Redmond, Paul and Taylor, Adele and Page, Danielle and Corley, Janie and Harris, Sarah E. and Tay, Darwin and Deary, Ian J. and Evans, Kathryn L. and Robinson, Matthew Richard and Chambers, John C. and Loh, Marie and Cox, Simon R. and Marioni, Riccardo E. and Hillary, Robert F.},
  issn         = {1537-6605},
  journal      = {American Journal of Human Genetics},
  number       = {1},
  pages        = {106--115},
  publisher    = {Elsevier},
  title        = {{DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts}},
  doi          = {10.1016/j.ajhg.2024.11.012},
  volume       = {112},
  year         = {2025},
}