Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

ABSTRACT

BACKGROUND: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation. METHODS: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls. RESULTS: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI) 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2 RERI = 1.74, p = 0.003; EUGEI RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2 RERI = 0.65, p = 0.284; EUGEI -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations NEMESIS-2 3.02, p < 0.001; EUGEI 6.44, p < 0.001; RERI delusional ideation NEMESIS-2 3.79, p < 0.001; EUGEI 5.43, p = 0.001; RERI hallucinatory experiences NEMESIS-2 2.46, p < 0.001; EUGEI 0.54, p = 0.465). CONCLUSIONS: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.