Epigenetic scores for the circulating proteome as tools for disease prediction
- University of Edinburgh, United Kingdom
- Virginia Tech, United States
- University of Oxford, United Kingdom
- The University of Texas at Austin, United States
- Helmholtz Zentrum München, Germany
- Max Planck Institute for Heart and Lung Research, Germany
- University of Queensland, Australia
- The University of Edinburgh, United Kingdom
- Weill Cornell Medical College in Qatar, Qatar
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
Riccardo E Marioni
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
- YM Dennis Lo, The Chinese University of Hong Kong, Hong Kong
Publication history
- Preprint posted: December 2, 2020 (view preprint)
- Received: June 30, 2021
- Accepted: January 11, 2022
- Accepted Manuscript published: January 13, 2022 (version 1)
- Version of Record published: February 25, 2022 (version 2)
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.
Metrics
-
- 3,095
- Page views
-
- 453
- Downloads
-
- 11
- Citations
Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Epigenetic scores for the circulating proteome as tools for disease prediction
eLife 11:e71802.
https://doi.org/10.7554/eLife.71802
Further reading
-
- Epidemiology and Global Health
Background:
Whether natural selection may have attributed to the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 infection. Associative studies of the RhD system and diseases are sparser. A large disease-wide risk analysis may further elucidate the relationship between the ABO/RhD blood groups and disease incidence.
Methods:
We performed a systematic log-linear quasi-Poisson regression analysis of the ABO/RhD blood groups across 1,312 phecode diagnoses. Unlike prior studies, we determined the incidence rate ratio for each individual ABO blood group relative to all other ABO blood groups as opposed to using blood group O as the reference. Moreover, we used up to 41 years of nationwide Danish follow-up data, and a disease categorization scheme specifically developed for diagnosis-wide analysis. Further, we determined associations between the ABO/RhD blood groups and the age at the first diagnosis. Estimates were adjusted for multiple testing.
Results:
The retrospective cohort included 482,914 Danish patients (60.4% females). The incidence rate ratios (IRRs) of 101 phecodes were found statistically significant between the ABO blood groups, while the IRRs of 28 phecodes were found statistically significant for the RhD blood group. The associations included cancers and musculoskeletal-, genitourinary-, endocrinal-, infectious-, cardiovascular-, and gastrointestinal diseases.
Conclusions:
We found associations of disease-wide susceptibility differences between the blood groups of the ABO and RhD systems, including cancer of the tongue, monocytic leukemia, cervical cancer, osteoarthrosis, asthma, and HIV- and hepatitis B infection. We found marginal evidence of associations between the blood groups and the age at first diagnosis.
Funding:
Novo Nordisk Foundation and the Innovation Fund Denmark
-
- Epidemiology and Global Health
- Genetics and Genomics
Background: To evaluate the utility of polygenic risk scores (PRS) in identifying high-risk individuals, different publicly available PRS for breast (n=85), prostate (n=37), colorectal (n=22) and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults.
Methods: We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals [CI] of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.
Results: A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal) and 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28-34% decreased risk compared to the middle quintile. In contrast, the hazard ratios observed for quintiles 4 (female-lung: 0.95 [0.61-1.47]; male-lung: 1.14 [0.82-1.57]) and 5 (female-lung: 0.95 [0.61-1.47]) were not significantly different from that for the middle quintile.
Conclusions: Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.
Funding This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022). The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health [NIH] (R01 CA144034 and UM1 CA182876).
