PT - JOURNAL ARTICLE AU - Thomas Battram AU - Rebecca C Richmond AU - Laura Baglietto AU - Philip C Haycock AU - Vittorio Perduca AU - Stig E Bojesen AU - Tom R Gaunt AU - Gibran Hemani AU - Florence Guida AU - Robert Carreras-Torres AU - Rayjean Hung AU - Christopher I Amos AU - Joshua R Freeman AU - Torkjel M Sandanger AU - Therese H Nøst AU - Børge Nordestgaard AU - Andrew E Teschendorff AU - Silvia Polidoro AU - Paolo Vineis AU - Gianluca Severi AU - Allison M Hodge AU - Graham G Giles AU - Kjell Grankvist AU - Mikael B Johansson AU - Mattias Johansson AU - George Davey Smith AU - Caroline L Relton TI - Appraising the causal relevance of DNA methylation for risk of lung cancer AID - 10.1101/287888 DP - 2019 Jan 01 TA - bioRxiv PG - 287888 4099 - http://biorxiv.org/content/early/2019/06/25/287888.short 4100 - http://biorxiv.org/content/early/2019/06/25/287888.full AB - Background DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.Methods We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29,863 cases and 55,586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.Results 16 CpG sites were identified from the EWAS meta-analysis (FDR < 0.05), 14 of which we could identify genetic instruments for. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites play a causal role in lung cancer development (FDR>0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.Conclusions The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.Key MessagesDNA methylation is a modifiable biomarker, giving it the potential to be targeted for intervention in many diseases, including lung cancer which is the most common cause of cancer-related death.This Mendelian randomization study attempted to evaluate whether there was a causal relationship, and thus potential for intervention, between DNA methylation measured in peripheral blood and lung cancer by assessing whether genetically altered DNA methylation levels impart differential lung cancer risks.Differential methylation at 14 CpG sites identified in epigenome-wide association analysis of lung cancer were assessed. Despite >99% power to detect the observational effect sizes, our Mendelian randomisation analysis gave little evidence that any of sites were causally linked to lung cancer.This is in stark contrast to previous analyses that suggested two CpG sites within the AHRR and F2RL3 locus, which were also observed in this analysis, mediate >30% of the effect of smoking on lung cancer.Overall findings suggest there is little or no role of differential methylation at the CpG sites identified within the blood in the development of lung cancer. Thus, targeting these sites for prevention of lung cancer is unlikely to yield effective treatments.