PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia.
Schizophrenia is a major mental illness affecting 1% of the population. It is known that genetics plays a role in the disease susceptibility, and it is thought that the illness is a complex disorder involving multiple genes. We show that the schizophrenia susceptibility gene, PRODH, conveys its risk through a variation that increases its enzyme activity. We further show that protection is associated with variations that decrease enzyme activity and these protective variations are enriched in their unaffected siblings. We then used brain imaging of structure and memory function to dissect the risk and protective haplotypes differential effects, and found that the schizophrenia risk haplotype was associated with decreased striatal gray matter volume and increased subcortical to frontal lobe functional connectivity, while the schizophrenia protective haplotype was associated with trend-level increase of frontal lobe volume and decreased subcortical to frontal lobe connectivity. These findings indicate a new target for treating schizophrenia and characterize associated structural and functional deficits.