Abstract
Presence or absence of recent stress preceding emergence of depressive symptoms may play a distinctive role in determining underlying etiological processes, explaining part of the significant heterogeneity characteristic of depression. Separately studying genetic associations of depressive symptoms appearing following, or independently of stress may help disentangle the genetic background of distinct depression subtypes in a general population sample. We included UK Biobank data (application number 1602) of nearly 120,000 subjects, and conducted three separate genome-wide analyses focusing on current depressive symptoms in three groups based on level of stress exposure in the past two years and analysed results from the aspect of neurobiological relationships between genetic variation and brain function. GWAS results were evaluated on SNP and gene-set levels. Heritability estimation revealed 10.4 %, 8.8 % and 5.1 % heritability in major-stress, minor-stress and no-stress groups, respectively. In the no-stress group 22, in the minor-stress group 22, and in the major-stress group 14 SNPs with suggestive significance were identified, with notable differences in the specific genes and processes implicated in the three groups. In the no-stress group marked association with long non-coding and micro-RNA emerged whereas in the major-stress group results implicate involvement of circadian genes and immunological pathways. Our findings reveal marked differences in the genetic underpinnings of depressive symptoms following exposure to different levels of recent stress, arguing that etiological heterogeneity of depression should be considered in both research and clinical applications, and pave the way of distinguishing between subtypes of depression based on the etiological contribution of stress.