Objectives:

1) To detect genetic variants reliably associated with depression in adolescents via genome-wide association approaches in the ALSPAC and TEDS cohorts

2) To identify observational associations between depression and modifiable risk factors using the Mendelian randomization approach

3) To investigate the association between depression and patterns in DNA methylation

Given the paucity of significant findings concerning depression, our first aim will be to investigate the genetic architecture of, and potentially identify genetic variants reliably associated with, depression in adolescents via a combination of genome-wide approaches within both the ALSPAC and TEDS cohorts.

The second aim will be to use genetic instruments to investigate causality in associations between modifiable or environmental risk factors and depression. First, literature searches will be used to identify important observational or proposed environmental exposures for depression. Several of these, such as vitamin D, glycaemic traits, inflammation and physical activity, are available in ALSPAC. Observational associations will be calculated and, for those modifiable risk factors with suitable genetic instruments, MR will be applied to determine whether the association is causal. The ARIES data will be used to investigate associations between exposure to maternal depression and patterns of methylation throughout early development. In particular, we aim to investigate whether early life stress events, such as antenatal and postnatal depression, have an effect on methylation patterns in the offspring. Independent associations between adolescent depression and both antenatal and postnatal depression have previously been shown, which appear to involve different mechanisms. We propose to explore whether this is mediated through DNA methylation.