1. Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function.
- Author
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Kempf L, Nicodemus KK, Kolachana B, Vakkalanka R, Verchinski BA, Egan MF, Straub RE, Mattay VA, Callicott JH, Weinberger DR, and Meyer-Lindenberg A
- Subjects
- Adult, Brain diagnostic imaging, Brain physiology, Female, Haplotypes, Humans, Magnetic Resonance Imaging, Male, Pedigree, Polymorphism, Single Nucleotide, Prefrontal Cortex diagnostic imaging, Proline Oxidase metabolism, Radiography, Risk Factors, Schizophrenia diagnostic imaging, Schizophrenia metabolism, Polymorphism, Genetic, Prefrontal Cortex metabolism, Prefrontal Cortex physiopathology, Proline Oxidase genetics, Schizophrenia genetics, Schizophrenia physiopathology
- Abstract
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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2008
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