Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants
Journal article, 2025
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.
Cardiovascular disease
Epigenetics
Biomarkers
Proteomics
Author
Josephine A. Robertson
University of Edinburgh
Jakub Bajzik
Institute of Science and Technology Austria
Spyros I. Vernardis
The Francis Crick Institute
Eliptica Limited
Aleksandra D. Chybowska
University of Edinburgh
Daniel L. McCartney
University of Edinburgh
Arturas Grauslys
Eliptica Limited
Jure Mur
University of Edinburgh
Hannah M. Smith
University of Edinburgh
Archie Campbell
Edinburgh Medical School
University of Edinburgh
Camilla Drake
Edinburgh Medical School, Medical Research Council Human Genetics Unit
Hannah Grant
University of Edinburgh
Jamie Pearce
University of Edinburgh
Tom C. Russ
Edinburgh Medical School
University of Edinburgh
Poppy Adkin
University College London (UCL)
The Francis Crick Institute
Matthew White
The Francis Crick Institute
Charles Brigden
Eliptica Limited
Christoph B. Messner
The Francis Crick Institute
University of Zürich
David J. Porteous
University of Edinburgh
Caroline Hayward
University of Edinburgh
Edinburgh Medical School, Medical Research Council Human Genetics Unit
Simon R. Cox
University of Edinburgh
Aleksej Zelezniak
Vilnius University
The Francis Crick Institute
Chalmers, Life Sciences, Systems and Synthetic Biology
Eliptica Limited
M. Ralser
The Francis Crick Institute
Charité University Medicine Berlin
Eliptica Limited
Matthew R. Robinson
Institute of Science and Technology Austria
Riccardo E. Marioni
University of Edinburgh
Genome Biology
1474-7596 (ISSN) 1474-760X (eISSN)
Vol. 26 1 417Subject Categories (SSIF 2025)
Medical Genetics and Genomics
Cardiology and Cardiovascular Disease
DOI
10.1186/s13059-025-03892-0
PubMed
41361833