{"language":[{"iso":"eng"}],"_id":"20816","title":"Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants","intvolume":"        26","quality_controlled":"1","publication_identifier":{"issn":["1474-7596"],"eissn":["1474-760X"]},"abstract":[{"lang":"eng","text":"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.\r\n\r\nResults: 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.\r\n\r\nConclusions: 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."}],"pmid":1,"oa":1,"publisher":"Springer Nature","date_created":"2025-12-14T23:02:04Z","doi":"10.1186/s13059-025-03892-0","article_number":"417","article_type":"original","scopus_import":"1","publication_status":"published","DOAJ_listed":"1","year":"2025","OA_place":"publisher","author":[{"last_name":"Robertson","full_name":"Robertson, Josephine A.","first_name":"Josephine A."},{"full_name":"Bajzik, Jakub","first_name":"Jakub","last_name":"Bajzik","id":"b995e25b-8c4b-11ed-a6d8-f71b7bcd6122"},{"first_name":"Spyros","full_name":"Vernardis, Spyros","last_name":"Vernardis"},{"full_name":"Chybowska, Aleksandra D.","first_name":"Aleksandra D.","last_name":"Chybowska"},{"last_name":"Mccartney","full_name":"Mccartney, Daniel L.","first_name":"Daniel L."},{"last_name":"Grauslys","full_name":"Grauslys, Arturas","first_name":"Arturas"},{"last_name":"Mur","full_name":"Mur, Jure","first_name":"Jure"},{"full_name":"Smith, Hannah M.","first_name":"Hannah M.","last_name":"Smith"},{"full_name":"Campbell, Archie","first_name":"Archie","last_name":"Campbell"},{"last_name":"Drake","full_name":"Drake, Camilla","first_name":"Camilla"},{"last_name":"Grant","first_name":"Hannah","full_name":"Grant, Hannah"},{"last_name":"Pearce","first_name":"Jamie","full_name":"Pearce, Jamie"},{"last_name":"Russ","full_name":"Russ, Tom C.","first_name":"Tom C."},{"last_name":"Adkin","full_name":"Adkin, Poppy","first_name":"Poppy"},{"last_name":"White","first_name":"Matthew","full_name":"White, Matthew"},{"first_name":"Charles","full_name":"Brigden, Charles","last_name":"Brigden"},{"last_name":"Messner","full_name":"Messner, Christoph B.","first_name":"Christoph B."},{"full_name":"Porteous, David J.","first_name":"David J.","last_name":"Porteous"},{"first_name":"Caroline","full_name":"Hayward, Caroline","last_name":"Hayward"},{"last_name":"Cox","full_name":"Cox, Simon R.","first_name":"Simon R."},{"first_name":"Aleksej","full_name":"Zelezniak, Aleksej","last_name":"Zelezniak"},{"last_name":"Ralser","first_name":"Markus","full_name":"Ralser, Markus"},{"id":"E5D42276-F5DA-11E9-8E24-6303E6697425","last_name":"Robinson","full_name":"Robinson, Matthew Richard","first_name":"Matthew Richard","orcid":"0000-0001-8982-8813"},{"full_name":"Marioni, Riccardo E.","first_name":"Riccardo E.","last_name":"Marioni"}],"acknowledgement":"Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the Generation Scotland samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). The DNA methylation profiling and analysis was supported by Wellcome Investigator Award 220857/Z/20/Z and Grant 104036/Z/14/Z (PI: Prof AM McIntosh) and through funding from NARSAD (Ref: 27404; awardee: Dr DM Howard) and the Royal College of Physicians of Edinburgh (Sim Fellowship; Awardee: Prof HC Whalley).\r\nJAR is a University of Edinburgh Clinical Academic Track PhD student, supported by the Wellcome Trust (319878/Z/24/Z). ADC was supported by a Medical Research Council PhD Studentship in Precision Medicine with funding from the Medical Research Council Doctoral Training Program and the University of Edinburgh College of Medicine and Veterinary Medicine. HMS is a student on the University of Edinburgh Translational Neuroscience PhD programme funded by the Wellcome Trust (218493/Z/19/Z). CH was funded by MRC Human Genetics Unit program (QTL in Health and Disease) (grant U.MC_UU_00007/10). S.R.C. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). JM and REM were supported by Alzheimer’s Society project grant AS-PG-19b-010.","month":"12","volume":26,"has_accepted_license":"1","license":"https://creativecommons.org/licenses/by/4.0/","date_updated":"2025-12-15T13:19:41Z","file":[{"date_created":"2025-12-15T13:18:07Z","access_level":"open_access","content_type":"application/pdf","file_id":"20825","checksum":"7c92919af1b5820d01e91e08906a411f","success":1,"file_name":"2025_GenomeBiology_Robertson.pdf","date_updated":"2025-12-15T13:18:07Z","file_size":2206991,"relation":"main_file","creator":"dernst"}],"publication":"Genome Biology","external_id":{"pmid":["41361833"]},"day":"08","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","OA_type":"gold","ddc":["570"],"article_processing_charge":"Yes","status":"public","citation":{"ista":"Robertson JA, Bajzik J, Vernardis S, Chybowska AD, Mccartney DL, Grauslys A, Mur J, Smith HM, Campbell A, Drake C, Grant H, Pearce J, Russ TC, Adkin P, White M, Brigden C, Messner CB, Porteous DJ, Hayward C, Cox SR, Zelezniak A, Ralser M, Robinson MR, Marioni RE. 2025. Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants. Genome Biology. 26, 417.","chicago":"Robertson, Josephine A., Jakub Bajzik, Spyros Vernardis, Aleksandra D. Chybowska, Daniel L. Mccartney, Arturas Grauslys, Jure Mur, et al. “Methylome-Wide Association Studies and Epigenetic Biomarker Development for 133 Mass Spectrometry-Assessed Circulating Proteins in 14,671 Generation Scotland Participants.” <i>Genome Biology</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1186/s13059-025-03892-0\">https://doi.org/10.1186/s13059-025-03892-0</a>.","apa":"Robertson, J. A., Bajzik, J., Vernardis, S., Chybowska, A. D., Mccartney, D. L., Grauslys, A., … Marioni, R. E. (2025). Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants. <i>Genome Biology</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s13059-025-03892-0\">https://doi.org/10.1186/s13059-025-03892-0</a>","ama":"Robertson JA, Bajzik J, Vernardis S, et al. Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants. <i>Genome Biology</i>. 2025;26. doi:<a href=\"https://doi.org/10.1186/s13059-025-03892-0\">10.1186/s13059-025-03892-0</a>","short":"J.A. Robertson, J. Bajzik, S. Vernardis, A.D. Chybowska, D.L. Mccartney, A. Grauslys, J. Mur, H.M. Smith, A. Campbell, C. Drake, H. Grant, J. Pearce, T.C. Russ, P. Adkin, M. White, C. Brigden, C.B. Messner, D.J. Porteous, C. Hayward, S.R. Cox, A. Zelezniak, M. Ralser, M.R. Robinson, R.E. Marioni, Genome Biology 26 (2025).","mla":"Robertson, Josephine A., et al. “Methylome-Wide Association Studies and Epigenetic Biomarker Development for 133 Mass Spectrometry-Assessed Circulating Proteins in 14,671 Generation Scotland Participants.” <i>Genome Biology</i>, vol. 26, 417, Springer Nature, 2025, doi:<a href=\"https://doi.org/10.1186/s13059-025-03892-0\">10.1186/s13059-025-03892-0</a>.","ieee":"J. A. Robertson <i>et al.</i>, “Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants,” <i>Genome Biology</i>, vol. 26. Springer Nature, 2025."},"file_date_updated":"2025-12-15T13:18:07Z","department":[{"_id":"MaRo"}],"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa_version":"Published Version","type":"journal_article","date_published":"2025-12-08T00:00:00Z"}