1. Epidemiology and Global Health
  2. Genetics and Genomics
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Epigenetic scores for the circulating proteome as tools for disease prediction

  1. Danni A Gadd
  2. Robert F Hillary
  3. Daniel L McCartney
  4. Shaza B Zaghlool
  5. Anna J Stevenson
  6. Yipeng Cheng
  7. Chloe Fawns-Ritchie
  8. Cliff Nangle
  9. Archie Campbell
  10. Robin Flaig
  11. Sarah E Harris
  12. Rosie M Walker
  13. Liu Shi
  14. Elliot M Tucker-Drob
  15. Christian Gieger
  16. Annette Peters
  17. Melanie Waldenberger
  18. Johannes Graumann
  19. Allan F McRae
  20. Ian J Deary
  21. David J Porteous
  22. Caroline Hayward
  23. Peter M Visscher
  24. Simon R Cox
  25. Kathryn L Evans
  26. Andrew M McIntosh
  27. Karsten Suhre
  28. Riccardo E Marioni  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Virginia Tech, United States
  3. University of Oxford, United Kingdom
  4. The University of Texas at Austin, United States
  5. Helmholtz Zentrum München, Germany
  6. Max Planck Institute for Heart and Lung Research, Germany
  7. University of Queensland, Australia
  8. The University of Edinburgh, United Kingdom
  9. Weill Cornell Medical College in Qatar, Qatar
Research Article
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Cite this article as: eLife 2022;11:e71802 doi: 10.7554/eLife.71802

Abstract

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore – disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

Data availability

Datasets generated in this study are made available in Supplementary file 1; this file includes the protein EpiScore weights for the 109 EpiScores we provide for future studies to use. All datasets used to create figures are included in Supplementary file 1 and specific locations for these are noted in figure legends.All code used in the analyses is available with open access at the following Gitlab repository: https://github.com/DanniGadd/EpiScores-for-protein-levels.The source datasets analysed during the current study are not publicly available due to them containing information that could compromise participant consent and confidentiality. Data can be obtained from the data owners. Instructions for Lothian Birth Cohort data access can be found here: https://www.lothianbirthcohort.ed.ac.uk/content/collaboration. Dr Simon Cox must be contacted to obtain a Lothian Birth Cohort 'Data Request Form' by email: simon.cox@ed.ac.uk. Instructions for accessing Generation Scotland data can be found here: https://www.ed.ac.uk/generation-scotland/for-researchers/access; the 'GS Access Request Form' can be downloaded from this site. Completed request forms must be sent to access@generationscotland.org to be approved by the Generation Scotland access committee. Data from the KORA study can be requested from KORA-gen: http://epi.helmholtz-muenchen.de/kora-gen. Requests are submitted online and are subject to approval by the KORA board.

Article and author information

Author details

  1. Danni A Gadd

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6398-5407
  2. Robert F Hillary

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  3. Daniel L McCartney

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  4. Shaza B Zaghlool

    Computer Engineering Department, Virginia Tech, Blacksburg, United States
    Competing interests
    No competing interests declared.
  5. Anna J Stevenson

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  6. Yipeng Cheng

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  7. Chloe Fawns-Ritchie

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  8. Cliff Nangle

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5432-1158
  9. Archie Campbell

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  10. Robin Flaig

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  11. Sarah E Harris

    Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4941-5106
  12. Rosie M Walker

    Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  13. Liu Shi

    Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  14. Elliot M Tucker-Drob

    Department of Psychology, The University of Texas at Austin, Austin, United States
    Competing interests
    No competing interests declared.
  15. Christian Gieger

    Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    No competing interests declared.
  16. Annette Peters

    Research Unit Molecular Epidemiology, Helmholtz Zentrum München, München, Germany
    Competing interests
    No competing interests declared.
  17. Melanie Waldenberger

    Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    No competing interests declared.
  18. Johannes Graumann

    Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  19. Allan F McRae

    Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
  20. Ian J Deary

    Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  21. David J Porteous

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  22. Caroline Hayward

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  23. Peter M Visscher

    Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
  24. Simon R Cox

    Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  25. Kathryn L Evans

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  26. Andrew M McIntosh

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  27. Karsten Suhre

    Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9638-3912
  28. Riccardo E Marioni

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Riccardo.Marioni@ed.ac.uk
    Competing interests
    Riccardo E Marioni, has received a speaker fee from Illumina and is an advisor to the Epigenetic Clock Development Foundation..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4430-4260

Funding

Wellcome Trust (108890/Z/15/Z)

  • Danni A Gadd
  • Robert F Hillary

Dementias Platform UK (MR/L023784/2)

  • Liu Shi

Medical Research Council (MC_UU_00007/10)

  • Caroline Hayward

Wellcome Trust (104036/Z/14/Z)

  • Ian J Deary
  • David J Porteous
  • Andrew M McIntosh

Wellcome Trust (220857/Z/20/Z)

  • Andrew M McIntosh

Wellcome Trust (216767/Z/19/Z)

  • Chloe Fawns-Ritchie
  • Cliff Nangle
  • Archie Campbell
  • Robin Flaig
  • Ian J Deary
  • David J Porteous
  • Caroline Hayward
  • Andrew M McIntosh
  • Riccardo E Marioni

Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6)

  • David J Porteous

Scottish Funding Council (HR03006)

  • David J Porteous

Australian Research Council Fellowship (FT200100837)

  • Allan F McRae

Australian Research Council (DP160102400,FL180100072)

  • Peter M Visscher

Australian National Health and Medical Research Council (1113400,1010374)

  • Peter M Visscher

Wellcome Trust (203771/Z/16/Z)

  • Anna J Stevenson

Medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1)

  • Ian J Deary

UK's Biotechnology and Biological Sciences Research Council

  • Ian J Deary

Royal Society-Wolfson Research Merit Award

  • Ian J Deary

Chief Scientist Office of the Scottish Government's Health Directorates

  • Ian J Deary

Age UK ((Disconnected Mind project))

  • Sarah E Harris
  • Ian J Deary
  • Simon R Cox

Medical Research Council (G0701120,G1001245,MR/M013111/1,MR/R024065/1)

  • Ian J Deary
  • Simon R Cox

Biotechnology and Biological Sciences Research Council (BB/F019394/1)

  • Ian J Deary

Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z)

  • Simon R Cox

National Institutes of Health (RF1AG073593,P2CHD042849,P30AG066614)

  • Elliot M Tucker-Drob

National Institutes of Health (R01AG054628)

  • Elliot M Tucker-Drob
  • Ian J Deary
  • Simon R Cox

Alzheimer's Research UK (ARUK-PG2017B−10)

  • Daniel L McCartney
  • Riccardo E Marioni

Health Data Research UK (substantive site award)

  • Archie Campbell

MRC Human Genetics Unit (MRC core support)

  • Caroline Hayward

Qatar Foundation (Biomedical Research Program at Weill Cornell Medicine)

  • Shaza B Zaghlool
  • Karsten Suhre

Qatar National Research Fund (NPRP11C-0115-180010)

  • Shaza B Zaghlool
  • Karsten Suhre

German Federal Ministry of Education and Research (Helmholtz Zentrum München)

  • Christian Gieger
  • Annette Peters
  • Melanie Waldenberger
  • Johannes Graumann

Munich Center of Health Sciences (LMUinnovativ)

  • Christian Gieger
  • Annette Peters
  • Melanie Waldenberger
  • Johannes Graumann

Bavarian State Ministry of Health and Care (DigiMed Bayern)

  • Christian Gieger
  • Annette Peters
  • Melanie Waldenberger
  • Johannes Graumann

NIHR Biomedical Research Centre at Oxford Health NHS Foundation Trust

  • Liu Shi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All KORA participants have given written informed consent and the study was approved by the Ethics Committee of the Bavarian Medical Association.All components of GS received ethical approval from the NHS Tayside Committee on Medical Research Ethics (REC Reference Number: 05/S1401/89). GS has also been granted Research Tissue Bank status by the East of Scotland Research Ethics Service (REC Reference Number: 20/ES/0021), providing generic ethical approval for a wide range of uses within medical research.Ethical approval for the LBC1921 and LBC1936 studies was obtained from the Multi-Centre Research Ethics Committee for Scotland (MREC/01/0/56) and the Lothian Research Ethics committee (LREC/1998/4/183; LREC/2003/2/29). In both studies, all participants provided written informed consent. These studies were performed in accordance with the Helsinki declaration.

Reviewing Editor

  1. YM Dennis Lo, The Chinese University of Hong Kong, Hong Kong

Publication history

  1. Received: June 30, 2021
  2. Accepted: January 11, 2022
  3. Accepted Manuscript published: January 13, 2022 (version 1)

Copyright

© 2022, Gadd et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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    Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings.

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    Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings.

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    Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).

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