BackgroundAltered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) ‘in rest’. We set out to test whether MCL-fc is conditional on (familial risk for) psychotic disorder and/or interactions with environmental exposures.MethodResting-state functional magnetic resonance imaging data were obtained from 63 patients with psychotic disorder, 73 non-psychotic siblings of patients with psychotic disorder and 59 healthy controls. With the nucleus accumbens (NAcc) as seed region, fc within the MCL system was estimated. Regression analyses adjusting for a priori hypothesized confounders were used to assess group differences in MCL connectivity as well as gene (group) × environmental exposure interactions (G × E) (i.e. to cannabis, developmental trauma and urbanicity).ResultsCompared with controls, patients and siblings had decreased fc between the right NAcc seed and the right orbitofrontal cortex (OFC) as well as the left middle cingulate cortex (MCC). Siblings showed decreased connectivity between the NAcc seed and lentiform nucleus compared with patients and controls. In addition, patients had decreased left NAcc connectivity compared with siblings in the left middle frontal gyrus. There was no evidence for a significant interaction between group and the three environmental exposures in the model of MCL-fc.ConclusionsReduced NAcc–OFC/MCC connectivity was seen in patients and siblings, suggesting that altered OFC connectivity and MCC connectivity are vulnerability markers for psychotic disorder. Differential exposure to environmental risk factors did not make an impact on the association between familial risk and MCL connectivity.