Genome-wide interaction study of stress-sensitivity and its prediction of major depressive disorder in UK Biobank and Generation Scotland

Stressful life events (SLE) are important predictors of neuroticism and the onset of major depressive disorder (MDD), complex traits involving both genetic and environmental factors. Identification of the genetics underpinning the individual differences in response to SLE may improve our understanding of molecular pathways involved, and the effects of stress-sensitivity on stress-related illnesses. We sought the combined effects of SLE on MDD status and neuroticism, as a proxy for stress-sensitivity, by modeling the interaction between SNP allele and MDD status on neuroticism score. We performed genome-wide interaction studies (GWIS) in UK Biobank (N = 23 092; UKB) and Generation Scotland: Scottish Family Health Study (N = 7 155; GS:SFHS). No SNP in the GWIS achieved genome-wide significance, but gene-based tests identified a genome-wide significant association between stress-sensitivity and ZNF366, a negative regulator of glucocorticoid receptor function that has been implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p