Evidence map›Paper›PMID 41361833›Full record

ArticleGenome biology2025

Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants.

Josephine A Robertson, Jakub Bajzik, Spyros Vernardis, Aleksandra D Chybowska, Daniel L McCartney, Arturas Grauslys, Jure Mur, Hannah M Smith, Archie Campbell, Camilla Drake and 14 more

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In one paragraph

Article in Genome biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Josephine A RobertsonInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Jakub BajzikInstitute of Science and Technology, Vienna, Austria.
Spyros VernardisMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
Aleksandra D ChybowskaInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Daniel L McCartneyInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Arturas GrauslysEliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK.
Jure MurInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Hannah M SmithInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Archie CampbellInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Camilla DrakeMRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Hannah GrantInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Jamie PearceCentre for Research on Environment, Society and Health, School of Geosciences, University of Edinburgh, Edinburgh, UK.
Tom C RussDivision of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Poppy AdkinMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
Matthew WhiteMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
Charles BrigdenEliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK.
Christoph B MessnerMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
David J PorteousInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Caroline HaywardInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Simon R CoxDepartment of Psychology, The Lothian Birth Cohorts, University of Edinburgh, Edinburgh, UK.
Aleksej ZelezniakMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
Markus RalserMolecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.
Matthew R RobinsonInstitute of Science and Technology, Vienna, Austria.
Riccardo E MarioniInstitute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. riccardo.marioni@ed.ac.uk.

Funding

Alzheimer's Society AS-PG-19b-010Medical Research Scotland U.MC_UU_00007/10Wellcome TrustWellcome Trust 218493/Z/19/ZWellcome Trust 221890/Z/20/ZWellcome Trust 319878/Z/24/Z
6 · The paper itself

Abstract

backgroundDNA 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.

resultsMarginal 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.

conclusionsWe 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.

Indexed as

Blood ProteinsCardiovascular DiseasesDNA MethylationEpigenesis, GeneticEpigenomeBiomarkersCpG IslandsFemaleGenome-Wide Association StudyHumansMaleMass SpectrometryMiddle AgedProteomeScotlandBiomarkersBlood ProteinsProteomeBiomarkersCardiovascular diseaseEpigeneticsProteomics

Identifiers

PMID41361833
PMCPMC12683789

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.