Physical Activity and Genome-wide DNA Methylation: The REGICOR Study.

INTRODUCTION DNA methylation may be one of the biological mechanisms underlying the health benefits of physical activity (PA). Our objective was to determine the association between PA and genome-wide DNA methylation at CpG level. METHODS We designed a two-stage epigenome wide association study. In the discovery stage, we used 619 individuals from the REGICOR cohort. Next, we validated the CpGs suggestively associated with PA (p-value <10) in two independent populations (n=1,735 and 190, respectively). PA was assessed with validated questionnaires and classified as light (LPA), moderate (MPA), vigorous (VPA), moderate-vigorous (MVPA) and total PA (TPA). We examined linear and non-linear associations and meta-analyzed the results in the three populations. The linear associations were meta-analyzed with a fixed-effects model and the p-values of the non-linear associations with the Stouffer and Fisher methods. We established a p-value threshold that fulfilled Bonferroni criteria over the number of CpGs analyzed (0.05/421,940=1.185·10). RESULTS In the meta-analyses, two CpG sites had a statistically significant non-linear association with MVPA. cg24155427 (p-value=1.19·10), located in an intergenic region in chromosome 1, has been previously associated with smoking, lupus and aging. cg09565397 (p-value=1.59·10), located within DGAT1 in chromosome 8, encodes an enzyme involved in triacylglycerol synthesis and has been associated with body mass index. CONCLUSION This population-based study identified two new, differentially methylated CpG sites with a non-linear dose-response relationship to MVPA. These associations must be additionally validated and may be considered for further research on the biological mechanisms underlying health benefits of PA.