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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 Messages

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