The genetic architecture of schizophrenia is complex and involves multiple genes. A candidate gene for schizophrenia that has received extensive investigation, with conflicting results, is PRODH. PRODH is implicated in schizophrenia through a hemi-deletion syndrome located on chromosome 22q11 (Velo-Cardio-Facial syndrome, VCFS), which may be the strongest known risk factor for schizophrenia besides having a monozygotic twin with the disorder. Our investigation ranged from clinical genetic association to studies of the associated pathophysiology through a multimodal imaging approach to examine the impact of variation in PRODH on risk for schizophrenia and function and structure in human brain of neural circuits implicated in schizophrenia. Through the Clinical Brain Disorders Branch we have access to a large sample of healthy siblings, which allows us to differentiate between state and potential trait clinical phenomena, it also permits an investigation of the genetics of protection within a family. Because siblings within a family, each have the same likelihood of inheriting risk-associated and risk-protective alleles from their parents, it is reasonable to predict that healthy siblings will show distorted genetic transmission of protective alleles similarly to ill offspring and distorted transmission of risk-associated alleles. We have tested this in a study of the gene PRODH and its enzyme product, POX, as having a clear biological effect by showing distorted transmission to affected offspring in our families. We focused on the three alleles that have been confirmed to effect POX enzyme activity, and found significant over-transmission of the alleles related to increased POX activity to affected offspring. Conversely when we examined risk-protection, significant over-transmission of the alleles related to decreased POX activity was found in the unaffected healthy siblings. Using brain imaging of structure and memory function to dissect the risk and protective differential effects, we found that the schizophrenia risk alleles were associated with decreased striatal gray matter volume and increased subcortical to frontal lobe functional connectivity, while the schizophrenia risk-protective alleles were associated with increased frontal lobe volume and decreased subcortical to frontal lobe connectivity. While our experiments and control experiments suggest that it is the impact on POX function that is the event linking genetic variation in PRODH to risk for schizophrenia, brain structure and function and the biochemical and cellular events mediating these observations remain unknown. These findings indicate a new target for treating schizophrenia and characterization of structural and functional deficits. We will be adapting this novel strategy to identify protection associated alleles and genes (which may not be the same as risk- associated genes) related to unaffected status in our families in future studies. This approach has the potential to define new targets for treatment.
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