@article{20816,
  abstract     = {Background: DNA methylation (DNAm) can regulate gene expression, and its genome-wide patterns (epigenetic scores or EpiScores) can act as biomarkers for complex traits. The relative stability of methylation profiles may enable better assessment of chronic exposures compared to single time-point protein measures. We present the first large-scale epigenetic study of the highly-abundant serum proteome measured via ultra-high throughput mass spectrometry in 14,671 samples from the Generation Scotland cohort. We further demonstrate the first large-scale comparison of protein EpiScores and their respective proteins as predictors of incident cardiovascular disease.

Results: Marginal epigenome-wide association models, adjusting for age, sex, measurement batch, estimated white cell proportions, BMI, smoking and methylation principal components, reveal 15,855 significant CpG – protein associations across 125 of 133 proteins PBonferroni < 2.71 × 10-10. Bayesian epigenome-wide association studies of the same 133 proteins reveal 697 CpG-Protein associations (posterior inclusion probability > 0.95). 112 protein EpiScores correlate significantly with their respective protein in a holdout test-set. Of these, sixteen associate significantly with incident all-cause cardiovascular disease (Nevents=191) compared to one measured protein.

Conclusions: We highlight a complex interplay between the blood-based methylome and proteome. Importantly, we show that protein EpiScores correlate with measured proteins and demonstrate that the, as-yet understudied, high-abundance proteome may yield clinically relevant biomarkers. The protein EpiScores demonstrate more significant associations with cardiovascular disease than directly measured proteins, suggesting their potential as clinical biomarkers for monitoring or predicting disease risk. We suggest that biomarker development could be enhanced by the consideration of protein EpiScores alongside measured proteins.},
  author       = {Robertson, Josephine A. and Bajzik, Jakub and Vernardis, Spyros and Chybowska, Aleksandra D. and Mccartney, Daniel L. and Grauslys, Arturas and Mur, Jure and Smith, Hannah M. and Campbell, Archie and Drake, Camilla and Grant, Hannah and Pearce, Jamie and Russ, Tom C. and Adkin, Poppy and White, Matthew and Brigden, Charles and Messner, Christoph B. and Porteous, David J. and Hayward, Caroline and Cox, Simon R. and Zelezniak, Aleksej and Ralser, Markus and Robinson, Matthew Richard and Marioni, Riccardo E.},
  issn         = {1474-760X},
  journal      = {Genome Biology},
  publisher    = {Springer Nature},
  title        = {{Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants}},
  doi          = {10.1186/s13059-025-03892-0},
  volume       = {26},
  year         = {2025},
}