Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity.

169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP.

Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP.

These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.