DNA methylation of core clock genes in patients with major depressive disorder: Association with air pollution exposure and disease severity

Background: Major Depressive Disorder (MDD) is a multifactorial disease which could be influenced by exposure to air pollution through disruption of sleep-wake cycles and other circadian-related behaviors. Our study aimed to investigate the interplay between air pollution exposure, DNA methylation of core clock genes involved in circadian rhythms, and MDD severity. Methods: Four hundred sixteen MDD patients (64 % females) agreed to participate and donated a blood sample to measure DNA methylation of the core clock genes CRY1, PER1, PER2, CLOCK, BMAL1. MDD severity and functioning was assessed using five rating scales. Daily mean estimates of particulate matter with diameter ≤ 2.5 μm (PM2.5) and nitrogen dioxide (NO2) were assigned to study participants based on their residential address, and averaged to estimate different cumulative exposure windows. Multivariate regression models were applied to assess associations between air pollutants and core clock genes methylation and between DNA methylation of those same genes and MDD severity. Results: PM2.5 exposure in the six months preceding recruitment was associated with CLOCK hypomethylation (β=-0.11, 95 % confidence interval [CI]:0.20; -0.02) and CRY1 hypermethylation (β=0.32, 95 %CI: 0.06; 0.58). All NO2 exposure windows were associated with CRY1 hypermethylation. Increasing methylation of CLOCK was associated with lower MDD severity considering several scales (e.g., Hamilton Depression Rating Scale: β=-7.21, 95 %CI:3.97; -0.44). Conclusions: Taken together our findings shed some light on the complex mechanism underlying the pathogenesis of MDD, with a potentially relevant role of the environment and of its impact on epigenetic mechanisms altering the expression of core clock genes.