DNA Methylation Mediates the Association Between Early Life Adversity and Childhood Depression

Abstract

Early life adversity can have long term consequences on wellbeing, including an increased risk of childhood depression. One mechanism proposed for this association is epigenetic modifications. These effects may be mediated by changes in DNA methylation at genes affecting disease predisposition. Methylation of the glucocorticoid receptor (NR3C1), a stress response gene, has been associated with depression. It is hypothesised that DNA methylation may mediate the effect due to early life adversity resulting in depression in New Zealand children. This study was undertaken using data from the longitudinal study Growing Up in New Zealand. The association between adversity and depression was investigated using the full cohort of 6953 children. Methylation of the NR3C1 locus was investigated in a 766 participant subset and a pilot genome-wide methylation investigation in 58 Māori participants. Maternal, family and neighbourhood stressors were reported on during pregnancy and at nine months post-natal and analysed in a cumulative design. Depression was measured at age eight years using the Centre for Epidemiologic Studies Depression Scale (CES-DC). DNA methylation was assayed in DNA extracted from saliva collected at age 4.5 years. The NR3C1 candidate gene subset was assayed with the EPITYPER and the genome wide pilot was assayed on EPIC chips. Adversity was found to be associated with increased risk of depression symptoms across both the full cohort (1.2 fold increase, p-value = 4.01e-06) and within the subset selected for NR3C1 DNA methylation assessment (1.16 fold increase, p-value = 0.016). The data from the EPITYPER array, which was undertaken by a service provider, had significant quality issues which were uncovered after considerable investigation. The pilot EPIC chip analysis revealed 12 CpG sites differentially methylated by depression phenotypes. 11 of these sites likely included common polymorphisms, and it remains to be determined if the DNA variation or methylation are the underlying mechanistic link. Excitingly, the remaining CpG site resides within the ERGIC1 gene, previously found to be associated with various neurological conditions. This is the first study to assess early life adversity and depression in NZ children, providing evidence that early life adversity is linked to poor outcomes in early life. The EPIC chip approach was a technical success revealing epigenetic-genetic associations with child depression suggesting a larger study is warranted.