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000179790 1001_ $$00000-0002-8237-2021$$aMorales Berstein, Fernanda$$b0
000179790 245__ $$aAssessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.
000179790 260__ $$aCambridge$$beLife Sciences Publications$$c2022
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000179790 520__ $$aEpigenetic 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.
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000179790 650_7 $$2Other$$aDNA methylation
000179790 650_7 $$2Other$$aMendelian randomization
000179790 650_7 $$2Other$$acancer
000179790 650_7 $$2Other$$aepidemiology
000179790 650_7 $$2Other$$aepigenetic age acceleration
000179790 650_7 $$2Other$$aepigenetic clocks
000179790 650_7 $$2Other$$agenetics
000179790 650_7 $$2Other$$agenomics
000179790 650_7 $$2Other$$ahuman
000179790 650_7 $$2Other$$amedicine
000179790 650_2 $$2MeSH$$aColorectal Neoplasms: epidemiology
000179790 650_2 $$2MeSH$$aColorectal Neoplasms: genetics
000179790 650_2 $$2MeSH$$aEpigenesis, Genetic
000179790 650_2 $$2MeSH$$aGenome-Wide Association Study: methods
000179790 650_2 $$2MeSH$$aHumans
000179790 650_2 $$2MeSH$$aMale
000179790 650_2 $$2MeSH$$aMendelian Randomization Analysis
000179790 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000179790 7001_ $$aMcCartney, Daniel L$$b1
000179790 7001_ $$aLu, Ake T$$b2
000179790 7001_ $$aTsilidis, Konstantinos K$$b3
000179790 7001_ $$aBouras, Emmanouil$$b4
000179790 7001_ $$00000-0001-5001-3350$$aHaycock, Philip$$b5
000179790 7001_ $$aBurrows, Kimberley$$b6
000179790 7001_ $$aPhipps, Amanda I$$b7
000179790 7001_ $$aBuchanan, Daniel D$$b8
000179790 7001_ $$aCheng, Iona$$b9
000179790 7001_ $$aconsortium, PRACTICAL$$b10$$eCollaboration Author
000179790 7001_ $$00000-0002-7992-7719$$aMartin, Richard M$$b11
000179790 7001_ $$00000-0002-1407-8314$$aDavey Smith, George$$b12
000179790 7001_ $$00000-0003-2052-4840$$aRelton, Caroline L$$b13
000179790 7001_ $$aHorvath, Steve$$b14
000179790 7001_ $$00000-0003-4430-4260$$aMarioni, Riccardo E$$b15
000179790 7001_ $$00000-0002-7918-2040$$aRichardson, Tom G$$b16
000179790 7001_ $$aRichmond, Rebecca C$$b17
000179790 7001_ $$aEeles, Rosalind A$$b18
000179790 7001_ $$aHaiman, Christopher A$$b19
000179790 7001_ $$aKote-Jarai, Zsofia$$b20
000179790 7001_ $$aSchumacher, Fredrick R$$b21
000179790 7001_ $$aBenlloch, Sara$$b22
000179790 7001_ $$aAl Olama, Ali Amin$$b23
000179790 7001_ $$aMuir, Kenneth R$$b24
000179790 7001_ $$aBerndt, Sonja I$$b25
000179790 7001_ $$aConti, David V$$b26
000179790 7001_ $$aWiklund, Fredrik$$b27
000179790 7001_ $$aChanock, Stephen$$b28
000179790 7001_ $$aWang, Ying$$b29
000179790 7001_ $$aTangen, Catherine M$$b30
000179790 7001_ $$aBatra, Jyotsna$$b31
000179790 7001_ $$aClements, Judith A$$b32
000179790 7001_ $$aApcb BioResource Australian Prostate Cancer BioResource$$b33
000179790 7001_ $$aGrönberg, Henrik$$b34
000179790 7001_ $$aPashayan, Nora$$b35
000179790 7001_ $$aSchleutker, Johanna$$b36
000179790 7001_ $$aAlbanes, Demetrius$$b37
000179790 7001_ $$aWeinstein, Stephanie$$b38
000179790 7001_ $$aWolk, Alicja$$b39
000179790 7001_ $$aWest, Catharine M L$$b40
000179790 7001_ $$aMucci, Lorelei A$$b41
000179790 7001_ $$aCancel-Tassin, Géraldine$$b42
000179790 7001_ $$aKoutros, Stella$$b43
000179790 7001_ $$aSørensen, Karina Dalsgaard$$b44
000179790 7001_ $$aGrindedal, Eli Marie$$b45
000179790 7001_ $$aNeal, David E$$b46
000179790 7001_ $$aHamdy, Freddie C$$b47
000179790 7001_ $$aDonovan, Jenny L$$b48
000179790 7001_ $$aTravis, Ruth C$$b49
000179790 7001_ $$aHamilton, Robert J$$b50
000179790 7001_ $$aIngles, Sue Ann$$b51
000179790 7001_ $$aRosenstein, Barry S$$b52
000179790 7001_ $$aLu, Yong-Jie$$b53
000179790 7001_ $$aGiles, Graham G$$b54
000179790 7001_ $$aMacInnis, Robert J$$b55
000179790 7001_ $$aKibel, Adam S$$b56
000179790 7001_ $$aVega, Ana$$b57
000179790 7001_ $$aKogevinas, Manolis$$b58
000179790 7001_ $$aPenney, Kathryn L$$b59
000179790 7001_ $$aPark, Jong Y$$b60
000179790 7001_ $$aStanford, Janet L$$b61
000179790 7001_ $$aCybulski, Cezary$$b62
000179790 7001_ $$aNordestgaard, Børge G$$b63
000179790 7001_ $$aNielsen, Sune F$$b64
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000179790 7001_ $$aMaier, Christiane$$b66
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000179790 7001_ $$aJohn, Esther M$$b68
000179790 7001_ $$aTeixeira, Manuel R$$b69
000179790 7001_ $$aNeuhausen, Susan L$$b70
000179790 7001_ $$aDe Ruyck, Kim$$b71
000179790 7001_ $$aRazack, Azad$$b72
000179790 7001_ $$aNewcomb, Lisa F$$b73
000179790 7001_ $$aLessel, Davor$$b74
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000179790 7001_ $$aEsteban Castelao, Jose$$b79
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000179790 7001_ $$aMenegaux, Florence$$b81
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