---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '20816'
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."
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."
article_number: '417'
article_processing_charge: Yes
article_type: original
author:
- first_name: Josephine A.
  full_name: Robertson, Josephine A.
  last_name: Robertson
- first_name: Jakub
  full_name: Bajzik, Jakub
  id: b995e25b-8c4b-11ed-a6d8-f71b7bcd6122
  last_name: Bajzik
- first_name: Spyros
  full_name: Vernardis, Spyros
  last_name: Vernardis
- first_name: Aleksandra D.
  full_name: Chybowska, Aleksandra D.
  last_name: Chybowska
- first_name: Daniel L.
  full_name: Mccartney, Daniel L.
  last_name: Mccartney
- first_name: Arturas
  full_name: Grauslys, Arturas
  last_name: Grauslys
- first_name: Jure
  full_name: Mur, Jure
  last_name: Mur
- first_name: Hannah M.
  full_name: Smith, Hannah M.
  last_name: Smith
- first_name: Archie
  full_name: Campbell, Archie
  last_name: Campbell
- first_name: Camilla
  full_name: Drake, Camilla
  last_name: Drake
- first_name: Hannah
  full_name: Grant, Hannah
  last_name: Grant
- first_name: Jamie
  full_name: Pearce, Jamie
  last_name: Pearce
- first_name: Tom C.
  full_name: Russ, Tom C.
  last_name: Russ
- first_name: Poppy
  full_name: Adkin, Poppy
  last_name: Adkin
- first_name: Matthew
  full_name: White, Matthew
  last_name: White
- first_name: Charles
  full_name: Brigden, Charles
  last_name: Brigden
- first_name: Christoph B.
  full_name: Messner, Christoph B.
  last_name: Messner
- first_name: David J.
  full_name: Porteous, David J.
  last_name: Porteous
- first_name: Caroline
  full_name: Hayward, Caroline
  last_name: Hayward
- first_name: Simon R.
  full_name: Cox, Simon R.
  last_name: Cox
- first_name: Aleksej
  full_name: Zelezniak, Aleksej
  last_name: Zelezniak
- first_name: Markus
  full_name: Ralser, Markus
  last_name: Ralser
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Riccardo E.
  full_name: Marioni, Riccardo E.
  last_name: Marioni
citation:
  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>
  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>
  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>.
  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.
  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.
  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>.
  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).
date_created: 2025-12-14T23:02:04Z
date_published: 2025-12-08T00:00:00Z
date_updated: 2025-12-15T13:19:41Z
day: '08'
ddc:
- '570'
department:
- _id: MaRo
doi: 10.1186/s13059-025-03892-0
external_id:
  pmid:
  - '41361833'
file:
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  creator: dernst
  date_created: 2025-12-15T13:18:07Z
  date_updated: 2025-12-15T13:18:07Z
  file_id: '20825'
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file_date_updated: 2025-12-15T13:18:07Z
has_accepted_license: '1'
intvolume: '        26'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
pmid: 1
publication: Genome Biology
publication_identifier:
  eissn:
  - 1474-760X
  issn:
  - 1474-7596
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Methylome-wide association studies and epigenetic biomarker development for
  133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland
  participants
tmp:
  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)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 26
year: '2025'
...
---
_id: '10702'
abstract:
- lang: eng
  text: 'Background: Blood-based markers of cognitive functioning might provide an
    accessible way to track neurodegeneration years prior to clinical manifestation
    of cognitive impairment and dementia. Results: Using blood-based epigenome-wide
    analyses of general cognitive function, we show that individual differences in
    DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function
    (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic
    score, in two external cohorts. It also associates with circulating levels of
    neurology- and inflammation-related proteins, global brain imaging metrics, and
    regional cortical volumes. Conclusions: As sample sizes increase, the ability
    to assess cognitive function from DNAm data may be informative in settings where
    cognitive testing is unreliable or unavailable.'
acknowledgement: 'GS received core support from the Chief Scientist Office of the
  Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council
  (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried
  out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility,
  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 data assayed for Generation
  Scotland was partially funded by a 2018 NARSAD Young Investigator Grant from the
  Brain & Behavior Research Foundation (Ref: 27404; awardee: Dr David M Howard) and
  by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh (Awardee:
  Dr Heather C Whalley). LBC1936 MRI brain imaging was supported by Medical Research
  Council (MRC) grants [G0701120], [G1001245], [MR/M013111/1] and [MR/R024065/1].
  Magnetic resonance image acquisition and analyses were conducted at the Brain Research
  Imaging Centre, Neuroimaging Sciences, University of Edinburgh (www.bric.ed.ac.uk)
  which is part of SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence)
  collaboration (www.sinapse.ac.uk) funded by the Scottish Funding Council and the
  Chief Scientist Office. This work was supported by the European Union Horizon 2020
  (PHC.03.15, project No 666881), SVDs@Target, the Fondation Leducq Transatlantic
  Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease
  [ref no. 16 CVD 05]. We thank the LBC1936 participants and team members who contributed
  to these studies. The LBC1936 is supported by Age UK (Disconnected Mind project,
  which supports S.E.H.), the Medical Research Council (G0701120, G1001245, MR/M013111/1,
  MR/R024065/1) and the University of Edinburgh. Methylation typing of LBC1936 was
  supported by the Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund
  award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University
  of Edinburgh, and The University of Queensland. Genotyping was funded by the Biotechnology
  and Biological Sciences Research Council (BB/F019394/1). Proteomic analyses in LBC1936
  were supported by the Age UK grant and NIH Grants R01AG054628 and R01AG05462802S1.
  M.V.H. is funded by the Row Fogo Charitable Trust (Grant no. BROD.FID3668413). J.M.W
  is supported by the UK Dementia Research Institute which receives its funding from
  DRI Ltd, funded by the UK Medical Research Council, Alzheimers Society and Alzheimers
  Research UK. R.F.H., E.L.S.C and D.A.G. are supported by funding from the Wellcome
  Trust 4 year PhD in Translational Neuroscience: training the next generation of
  basic neuroscientists to embrace clinical research [108890/Z/15/Z]. E.M.T.D. was
  supported by the National Institutes of Health (NIH) grants R01AG054628, R01MH120219,
  R01HD083613, P2CHD042849 and P30AG066614. S.R.C. was also supported by a National
  Institutes of Health (NIH) research grant R01AG054628 and is supported by a Sir
  Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society
  (Grant Number 221890/Z/20/Z). D.L.Mc.C. and R.E.M. are supported by Alzheimers Research
  UK major project grant ARUK/PG2017B/10. R.E.M. is supported by Alzheimer’s Society
  major project grant AS-PG-19b-010. This research was funded in whole, or in part,
  by Wellcome [104036/Z/14/Z and 108890/Z/15/Z]. For the purpose of open access, the
  author has applied a CC BY public copyright licence to any Author Accepted Manuscript
  version arising from this submission.'
article_number: '26'
article_processing_charge: No
article_type: original
author:
- first_name: Daniel L.
  full_name: McCartney, Daniel L.
  last_name: McCartney
- first_name: Robert F.
  full_name: Hillary, Robert F.
  last_name: Hillary
- first_name: Eleanor L.S.
  full_name: Conole, Eleanor L.S.
  last_name: Conole
- first_name: Daniel Trejo
  full_name: Banos, Daniel Trejo
  last_name: Banos
- first_name: Danni A.
  full_name: Gadd, Danni A.
  last_name: Gadd
- first_name: Rosie M.
  full_name: Walker, Rosie M.
  last_name: Walker
- first_name: Cliff
  full_name: Nangle, Cliff
  last_name: Nangle
- first_name: Robin
  full_name: Flaig, Robin
  last_name: Flaig
- first_name: Archie
  full_name: Campbell, Archie
  last_name: Campbell
- first_name: Alison D.
  full_name: Murray, Alison D.
  last_name: Murray
- first_name: Susana Muñoz
  full_name: Maniega, Susana Muñoz
  last_name: Maniega
- first_name: María Del C.
  full_name: Valdés-Hernández, María Del C.
  last_name: Valdés-Hernández
- first_name: Mathew A.
  full_name: Harris, Mathew A.
  last_name: Harris
- first_name: Mark E.
  full_name: Bastin, Mark E.
  last_name: Bastin
- first_name: Joanna M.
  full_name: Wardlaw, Joanna M.
  last_name: Wardlaw
- first_name: Sarah E.
  full_name: Harris, Sarah E.
  last_name: Harris
- first_name: David J.
  full_name: Porteous, David J.
  last_name: Porteous
- first_name: Elliot M.
  full_name: Tucker-Drob, Elliot M.
  last_name: Tucker-Drob
- first_name: Andrew M.
  full_name: McIntosh, Andrew M.
  last_name: McIntosh
- first_name: Kathryn L.
  full_name: Evans, Kathryn L.
  last_name: Evans
- first_name: Ian J.
  full_name: Deary, Ian J.
  last_name: Deary
- first_name: Simon R.
  full_name: Cox, Simon R.
  last_name: Cox
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Riccardo E.
  full_name: Marioni, Riccardo E.
  last_name: Marioni
citation:
  ama: McCartney DL, Hillary RF, Conole ELS, et al. Blood-based epigenome-wide analyses
    of cognitive abilities. <i>Genome Biology</i>. 2022;23(1). doi:<a href="https://doi.org/10.1186/s13059-021-02596-5">10.1186/s13059-021-02596-5</a>
  apa: McCartney, D. L., Hillary, R. F., Conole, E. L. S., Banos, D. T., Gadd, D.
    A., Walker, R. M., … Marioni, R. E. (2022). Blood-based epigenome-wide analyses
    of cognitive abilities. <i>Genome Biology</i>. Springer Nature. <a href="https://doi.org/10.1186/s13059-021-02596-5">https://doi.org/10.1186/s13059-021-02596-5</a>
  chicago: McCartney, Daniel L., Robert F. Hillary, Eleanor L.S. Conole, Daniel Trejo
    Banos, Danni A. Gadd, Rosie M. Walker, Cliff Nangle, et al. “Blood-Based Epigenome-Wide
    Analyses of Cognitive Abilities.” <i>Genome Biology</i>. Springer Nature, 2022.
    <a href="https://doi.org/10.1186/s13059-021-02596-5">https://doi.org/10.1186/s13059-021-02596-5</a>.
  ieee: D. L. McCartney <i>et al.</i>, “Blood-based epigenome-wide analyses of cognitive
    abilities,” <i>Genome Biology</i>, vol. 23, no. 1. Springer Nature, 2022.
  ista: McCartney DL, Hillary RF, Conole ELS, Banos DT, Gadd DA, Walker RM, Nangle
    C, Flaig R, Campbell A, Murray AD, Maniega SM, Valdés-Hernández MDC, Harris MA,
    Bastin ME, Wardlaw JM, Harris SE, Porteous DJ, Tucker-Drob EM, McIntosh AM, Evans
    KL, Deary IJ, Cox SR, Robinson MR, Marioni RE. 2022. Blood-based epigenome-wide
    analyses of cognitive abilities. Genome Biology. 23(1), 26.
  mla: McCartney, Daniel L., et al. “Blood-Based Epigenome-Wide Analyses of Cognitive
    Abilities.” <i>Genome Biology</i>, vol. 23, no. 1, 26, Springer Nature, 2022,
    doi:<a href="https://doi.org/10.1186/s13059-021-02596-5">10.1186/s13059-021-02596-5</a>.
  short: D.L. McCartney, R.F. Hillary, E.L.S. Conole, D.T. Banos, D.A. Gadd, R.M.
    Walker, C. Nangle, R. Flaig, A. Campbell, A.D. Murray, S.M. Maniega, M.D.C. Valdés-Hernández,
    M.A. Harris, M.E. Bastin, J.M. Wardlaw, S.E. Harris, D.J. Porteous, E.M. Tucker-Drob,
    A.M. McIntosh, K.L. Evans, I.J. Deary, S.R. Cox, M.R. Robinson, R.E. Marioni,
    Genome Biology 23 (2022).
corr_author: '1'
date_created: 2022-01-30T23:01:33Z
date_published: 2022-01-17T00:00:00Z
date_updated: 2025-06-11T13:54:53Z
day: '17'
ddc:
- '570'
department:
- _id: MaRo
doi: 10.1186/s13059-021-02596-5
external_id:
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month: '01'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 9B8D11D6-BA93-11EA-9121-9846C619BF3A
  grant_number: PCEGP3_181181
  name: Improving estimation and prediction of common complex disease risk
publication: Genome Biology
publication_identifier:
  eissn:
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  issn:
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publication_status: published
publisher: Springer Nature
quality_controlled: '1'
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scopus_import: '1'
status: public
title: Blood-based epigenome-wide analyses of cognitive abilities
tmp:
  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)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 23
year: '2022'
...