Pathways to schizophrenia: Divergent effects of childhood trauma and polygenic risk on cognition and subcortical dynamics

Background: Schizophrenia is often a persistent mental illness characterized by cognitive deficits and altered brain network dynamics especially affecting the corticosubcortical salience processing system.Childhood trauma has been implicated in mechanisms contributing to schizophrenia, but the role of genetic vulnerability remains unclear.Methods: A total of 164 schizophrenia patients and 114 healthy controls were included.First, a matched subsample of 117 patients (76 with and 41 without childhood trauma), and 59 healthy controls were compared on polygenic risk scores for schizophrenia (SczPRS).SczPRS was then correlated with neurocognitive performance using a comprehensive cognitive battery (n=147 patients) and brain-wide static and dynamic functional connectivity (sFC and dFC) using resting-state fMRI (n=117 patients).Patients were also stratified into high-SczPRS and low-SczPRS (n=25 each) subgroups. Results:Patients with childhood trauma had significantly lower SczPRS than those without.Higher CTQ scores related to lower cognitive PC score (r = -0.282,p < 0.001), but CTQ didn't affect brain-wide dysconnectivity or subcortical/salience system among patients.Patients with highest SczPRS showed lower dFC between the cinguloopercular network (CON) and subcortical networks (SUB) (F = 7.949, p = 0.007), but SczPRS didn't affect cognitive performance. Conclusions:Our findings reveal distinct effects of childhood trauma and polygenic risk in the neural and cognitive substrates of schizophrenia.