Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

  1. Fernanda Morales Berstein  Is a corresponding author
  2. Daniel L McCartney
  3. Ake T Lu
  4. Konstantinos K Tsilidis
  5. Emmanouil Bouras
  6. Philip C Haycock
  7. Kimberley Burrows
  8. Amanda I Phipps
  9. Daniel D Buchanan
  10. Iona Cheng
  11. The PRACTICAL Consortium
  12. Richard M Martin
  13. George Davey Smith
  14. Caroline L Relton
  15. Steve Horvath
  16. Riccardo E Marioni
  17. Tom G Richardson
  18. Rebecca C Richmond
  1. University of Bristol, United Kingdom
  2. University of Edinburgh, United Kingdom
  3. University of California, Los Angeles, United States
  4. Imperial College London, United Kingdom
  5. University of Ioannina, Greece
  6. Fred Hutchinson Cancer Research Center, United States
  7. University of Melbourne, Australia
  8. Cancer Prevention Institute of California, United States

Abstract

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.

Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (9 single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs) and GrimAge (4 SNPs) on multiple cancers (i.e., breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N=34,710), and for cancer from the UK Biobank (N cases=2,671-13,879; N controls=173,493-372,016), FinnGen (N cases=719-8,401; N controls=74,685-174,006) and several international cancer genetic consortia (N cases=11,348-122,977; N controls=15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.

Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR=1.12 per year increase in GrimAge acceleration, 95%CI 1.04-1.20, p=0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR=1.15, 95%CI 1.09-1.21, p=0.006), than rectal cancer (IVW OR=1.05, 95%CI 0.97-1.13, p=0.24). Results were less consistent for associations between other epigenetic clocks and cancers.

Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.

Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.

Data availability

Summary statistics for epigenetic age acceleration measures of HannumAge, Intrinsic HorvathAge, PhenoAge and GrimAge were downloaded from: https://datashare.ed.ac.uk/handle/10283/3645. Summary statistics for international cancer genetic consortiums were obtained from their respective data repositories. Colorectal cancer data were obtained following the submission of a written request to the GECCO committee, which may be contacted by email at kafdem@fredhutch.org/upeters@fredhutch.org. Breast, ovarian, prostate and lung cancer data were accessed via MR-Base (http://app.mrbase.org/), which holds complete GWAS summary data from BCAC, OCAC, PRACTICAL and ILCCO. Breast cancer subtype data were obtained from BCAC and can be downloaded from: http://bcac.ccge.medschl.cam.ac.uk/bcacdata/oncoarray/oncoarray-and-combined-summary-result/gwas-summary-associations-breast-cancer-risk-2020/. Data on breast and ovarian cancer in BRCA1 and BRCA2 carriers were obtained from CIMBA and can be downloaded from: http://cimba.ccge.medschl.cam.ac.uk/oncoarray-complete-summary-results/. Prostate cancer subtype data are not publicly available through MR-Base but can be accessed upon request. These data are managed by the PRACTICAL committee, which may be contacted by email at practical@icr.ac.uk. FinnGen data is publicly available and can be accessed here: https://www.finngen.fi/en/access_results. UK Biobank data can be accessed through the MR-Base platform. Parental history of cancer data were obtained from the UK Biobank study under application #15825 and can be accessed via an approved application to the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). GWAS data for negative control outcomes and potential confounders were obtained via the MR-Base platform (GWAS IDs for negative control outcomes: "ukb-b-19560", "ukb-b-533"; GWAS IDs for confounders: "ukb-b-10831", "ukb-b-13702", "ukb-b-6134", "ieu-a-1239", "ukb-b-5779", "ieu-a-835", "ieu-a-61"). GWAS data for measured telomere length used in bidirectional MR analyses were also obtained via the MR-Base platform (GWAS ID: "ieu-b-4879").

The following previously published data sets were used
    1. FinnGen consortium
    (2021) Colorectal cancer (all cancers excluded)
    FinnGen public data r5, finngen_R5_C3_COLORECTAL_EXALLC.gz.

Article and author information

Author details

  1. Fernanda Morales Berstein

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    For correspondence
    dy20206@bristol.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8237-2021
  2. Daniel L McCartney

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  3. Ake T Lu

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Ake T Lu, declares that UC Regents filed the patent DNA METHYLATION BASED BIOMARKERS FOR LIFE EXPECTANCY AND MORBIDITY" (International Application Number PCT/US2019/055444; in pending status) and that the Epigenetic Clock Development Foundation and Foxo Labs hold licenses.".
  4. Konstantinos K Tsilidis

    Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Emmanouil Bouras

    Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
    Competing interests
    No competing interests declared.
  6. Philip C Haycock

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5001-3350
  7. Kimberley Burrows

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
  8. Amanda I Phipps

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  9. Daniel D Buchanan

    Department of Clinical Pathology, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.
  10. Iona Cheng

    Cancer Prevention Institute of California, Fremont, United States
    Competing interests
    No competing interests declared.
  11. The PRACTICAL Consortium

  12. Richard M Martin

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7992-7719
  13. George Davey Smith

    Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1407-8314
  14. Caroline L Relton

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2052-4840
  15. Steve Horvath

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Steve Horvath, declares that UC Regents filed the patent DNA METHYLATION BASED BIOMARKERS FOR LIFE EXPECTANCY AND MORBIDITY" (International Application Number PCT/US2019/055444; in pending status) and that the Epigenetic Clock Development Foundation and Foxo Labs hold licenses. SH receives consulting fees from the Epigenetic Clock Development Foundation and royalties for patents involving epigenetic clocks.".
  16. Riccardo E Marioni

    Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
    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
  17. Tom G Richardson

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    Tom G Richardson, is employed part time by Novo Nordisk outside of this work..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7918-2040
  18. Rebecca C Richmond

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.

Funding

Wellcome Trust (224982/Z/22/Z)

  • Fernanda Morales Berstein

Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5)

  • George Davey Smith

Cancer Research UK (C18281/A29019)

  • Caroline L Relton

Cancer Research UK (C18281/A29019)

  • George Davey Smith

Alzheimer's Society (AS-PG-19b-010)

  • Riccardo E Marioni

National Institutes of Health (U01 AG-18-018,PI: Steve Horvath)

  • Riccardo E Marioni

de Pass Vice Chancellor's Research Fellow at the University of Bristol

  • Rebecca C Richmond

Cancer Research UK (C18281/A29019)

  • Konstantinos K Tsilidis

Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228)

  • Konstantinos K Tsilidis

Cancer Research UK (C18281/A29019)

  • Philip C Haycock

Cancer Research UK (C18281/A29019)

  • Richard M Martin

NIHR Biomedical Research Centre at University Hospitals Bristol

  • Richard M Martin

Weston NHS Foundation Trust

  • Richard M Martin

NIHR Senior Investigator (NIHR202411)

  • Richard M Martin

Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5)

  • Caroline L Relton

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

Reviewing Editor

  1. Maroeska M Rovers, Radboud University Nijmegen, Netherlands

Ethics

Human subjects: This research did not require ethical approval as it used secondary, genome-wide association data from studies that obtained informed consent from all participants and ethical approval from review boards and/or ethics committees.

Version history

  1. Received: November 8, 2021
  2. Preprint posted: December 7, 2021 (view preprint)
  3. Accepted: March 10, 2022
  4. Accepted Manuscript published: March 29, 2022 (version 1)
  5. Version of Record published: April 28, 2022 (version 2)
  6. Version of Record updated: May 13, 2022 (version 3)

Copyright

© 2022, Morales Berstein 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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  1. Fernanda Morales Berstein
  2. Daniel L McCartney
  3. Ake T Lu
  4. Konstantinos K Tsilidis
  5. Emmanouil Bouras
  6. Philip C Haycock
  7. Kimberley Burrows
  8. Amanda I Phipps
  9. Daniel D Buchanan
  10. Iona Cheng
  11. The PRACTICAL Consortium
  12. Richard M Martin
  13. George Davey Smith
  14. Caroline L Relton
  15. Steve Horvath
  16. Riccardo E Marioni
  17. Tom G Richardson
  18. Rebecca C Richmond
(2022)
Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study
eLife 11:e75374.
https://doi.org/10.7554/eLife.75374

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https://doi.org/10.7554/eLife.75374

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