An Epigenome-Wide Association Study (EWAS) of Obesity-Related Traits.

We conducted an epigenome-wide association study on obesity-related traits. We used data from two prospective, population-based cohort studies: the Rotterdam Study (RS) (2006-2013) and the Atherosclerosis Risk in Communities (ARIC) Study (1990-1992). We used RS (n = 1,454) as the discovery panel and ARIC (n = 2,097) as replication panel. Linear mixed-effect models were used to assess the cross-sectional association between genome-wide DNA methylation in leukocytes with body mass index (BMI) and waist circumference (WC) adjusting for sex, age, smoking, leukocyte proportions, array number and position on array. The two latter were modelled as random effects. Fourteen CpGs were associated with BMI and 26 CpGs with WC in RS after Bonferroni-correction (P < 1.07 × 10-7), of which 12 and 13 CpGs replicated in ARIC Study, respectively. The most significant novel CpGs were located at MSI2 (cg21139312) and LARS2 (cg18030453) and were associated both with BMI and WC. CpGs at BRDT, PSMD1, IFI44L, MAP1A, and MAP3K5 were associated with BMI. CpGs at LGALS3BP, MAP2K3, DHCR24, CPSF4L, and TMEM49 were associated with WC. We report novel associations of methylation at MSI2 and LARS2 with obesity-related traits. These results provide further insight in mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases.