title: Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function.
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.
authors.affiliation: Department of Health and Human Services, Unit of Systems Neuroscience in Psychiatry, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lucas
authors.initials: L
authors.lastname: Kempf
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Nicodemus
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Vakkalanka
authors.forename: Beth A
authors.initials: BA
authors.lastname: Verchinski
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.forename: Venkata A
authors.initials: VA
authors.lastname: Mattay
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000502:physiology; D005260:Female; D006239:Haplotypes; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D011394:Proline Oxidase / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D012307:Risk Factors; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D011394:Proline Oxidase