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@ARTICLE{MoralesBerstein:179790,
author = {F. Morales Berstein and D. L. McCartney and A. T. Lu and K.
K. Tsilidis and E. Bouras and P. Haycock and K. Burrows and
A. I. Phipps and D. D. Buchanan and I. Cheng and R. M.
Martin and G. Davey Smith and C. L. Relton and S. Horvath
and R. E. Marioni and T. G. Richardson and R. C. Richmond
and R. A. Eeles and C. A. Haiman and Z. Kote-Jarai and F. R.
Schumacher and S. Benlloch and A. A. Al Olama and K. R. Muir
and S. I. Berndt and D. V. Conti and F. Wiklund and S.
Chanock and Y. Wang and C. M. Tangen and J. Batra and J. A.
Clements and Apcb BioResource Australian Prostate Cancer
BioResource and H. Grönberg and N. Pashayan and J.
Schleutker and D. Albanes and S. Weinstein and A. Wolk and
C. M. L. West and L. A. Mucci and G. Cancel-Tassin and S.
Koutros and K. D. Sørensen and E. M. Grindedal and D. E.
Neal and F. C. Hamdy and J. L. Donovan and R. C. Travis and
R. J. Hamilton and S. A. Ingles and B. S. Rosenstein and
Y.-J. Lu and G. G. Giles and R. J. MacInnis and A. S. Kibel
and A. Vega and M. Kogevinas and K. L. Penney and J. Y. Park
and J. L. Stanford and C. Cybulski and B. G. Nordestgaard
and S. F. Nielsen and H. Brenner$^*$ and C. Maier and U. Kim
and E. M. John and M. R. Teixeira and S. L. Neuhausen and K.
De Ruyck and A. Razack and L. F. Newcomb and D. Lessel and
R. Kaneva and N. Usmani and F. Claessens and P. A. Townsend
and J. Esteban Castelao and M. J. Roobol and F. Menegaux and
K.-T. Khaw and U. Cannon-Albright and H. Pandha and S. N.
Thibodeau and D. J. Hunter and P. Kraft and W. J. Blot and
E. Riboli},
collaboration = {P. consortium},
title = {{A}ssessing the causal role of epigenetic clocks in the
development of multiple cancers: a {M}endelian randomization
study.},
journal = {eLife},
volume = {11},
issn = {2050-084X},
address = {Cambridge},
publisher = {eLife Sciences Publications},
reportid = {DKFZ-2022-00897},
pages = {e75374},
year = {2022},
abstract = {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.We conducted a two-sample
Mendelian randomization (MR) study to examine the
genetically predicted effects of epigenetic age acceleration
as measured by HannumAge (nine 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 = 2671-13,879; N
controls = 173,493-372,016), FinnGen (N cases = 719-8401; 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.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.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.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 $MC_UU_00011/5,$ respectively) 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.},
keywords = {Colorectal Neoplasms: epidemiology / Colorectal Neoplasms:
genetics / Epigenesis, Genetic / Genome-Wide Association
Study: methods / Humans / Male / Mendelian Randomization
Analysis / Polymorphism, Single Nucleotide / DNA methylation
(Other) / Mendelian randomization (Other) / cancer (Other) /
epidemiology (Other) / epigenetic age acceleration (Other) /
epigenetic clocks (Other) / genetics (Other) / genomics
(Other) / human (Other) / medicine (Other)},
cin = {C070 / C120 / HD01},
ddc = {600},
cid = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
I:(DE-He78)HD01-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:35346416},
pmc = {pmc:PMC9049976},
doi = {10.7554/eLife.75374},
url = {https://inrepo02.dkfz.de/record/179790},
}
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