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

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). We also found evidence that higher GrimAge acceleration decreased the risk of prostate cancer (pooled IVW OR=0.93 per year increase in GrimAge acceleration, 95%CI 0.87-0.99, p=0.02). This was supported by MR sensitivity analyses, but did not replicate in MR analyses using data on parental history of prostate cancer in UK Biobank (IVW OR=1.00, 95%CI 0.96-1.04, p=1.00). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Additionally, there is more limited evidence that it may be protective against prostate 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 (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 Republics Operational Programme "Competitiveness, Entrepreneurship & Innovation" (O{Pi}{Sigma} 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). 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 Chancellors Research Fellow at the University of Bristol.