Body mass index and lung function: A two-step epigenetic Mendelian randomization study

<b>Background:</b> A Mendelian randomisation (MR) study and longitudinal studies have reported the association of lung function with body mass index (BMI). <b>Aim:</b> To investigate whether the association of lung function with BMI is mediated by DNA methylation. <b>Methods:</b> Using data from population-based cohorts (ECRHS, NFBC, SAPALDIA) from the Ageing Lungs in European Cohorts (ALEC) consortium and summary data from published studies, we assessed the mediating role of DNA methylation in the association of lung function with BMI using a 2-step epigenetic MR approach. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level, i.e. &gt;450k CpGs), using 97 BMI-associated SNPs as instrumental variables for BMI in 2,134 participants. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC in 7,577 participants (not included in the 1st step) from the same cohorts. As instrumental variables, in this step, we used independent SNPs occurring close (in <i>cis</i>) to 2 CpGs identified in the first step. MR estimates were derived using the Wald ratio, with standard error from the delta method. <b>Results:</b> In step 1, we found that BMI has a small causal effect on DNA methylation levels (less than 1% change in methylation per 1-unit increase in BMI) at 17 CpGs. Of these CpGs, just two were significantly associated with cis-SNPs. In step 2, we found little evidence of a causal effect of DNA methylation at these two sites on lung function. <b>Conclusion:</b> Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI. However, we were underpowered to detect small effects. <b>Funding:</b> EU H2020 #633212