Stressful experiences trigger adaptive behavioural responses. In vertebrates, these changes are mediated by the hypothalamic-pituitary-adrenal (HPA) circuit. Excess stress during critical periods of development affects brain maturation, which in humans has been linked to the development of adult-onset neuropsychiatric disorders. Evidence from animal models has demonstrated that stress in early life can have effects on behaviour, endocrine function and gene expression, which may be mediated by epigenetic imprints that persist into adulthood. In addition, there is a growing literature supporting a role for gene-environment (GxE) interactions in the pathogenesis of psychiatric disease. The zebrafish is becoming an increasingly popular model in behavioural neuroscience and lends itself to high-throughput behaviour-based screens. The work presented here utilizes a zebrafish GxE model and investigates the role for an orthologue of a genetic risk factor for psychiatric illness in humans (Disrupted-In-Schizophrenia 1, DISC1) in the stress response. Our data suggest that zebrafish disc1 mutants display abnormal endocrine and behavioural responses to a chemical stressor, which are mediated by an interaction between disc1 and key hypothalamic genes. This evidence supports a role for DISC1 in behavioural responses to stress.