Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function

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...

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Published in:PLoS genetics 2008-11, Vol.4 (11), p.e1000252-e1000252
Main Authors: Kempf, Lucas, Nicodemus, Kristin K, Kolachana, Bhaskar, Vakkalanka, Radhakrishna, Verchinski, Beth A, Egan, Michael F, Straub, Richard E, Mattay, Venkata A, Callicott, Joseph H, Weinberger, Daniel R, Meyer-Lindenberg, Andreas
Format: Article
Language:English
Subjects:
Adult
Brain - diagnostic imaging
Brain - physiology
Female
Genes
Genetic aspects
Genetics
Genetics and Genomics/Medical Genetics
Haplotypes
Health risk assessment
Humans
Illnesses
Magnetic Resonance Imaging
Male
Mental disorders
Neurological Disorders/Neurogenetics
Neurological Disorders/Neuroimaging
Oxidoreductases
Pedigree
Physiological aspects
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Prefrontal Cortex - diagnostic imaging
Prefrontal Cortex - metabolism
Prefrontal Cortex - physiopathology
Proline Oxidase - genetics
Proline Oxidase - metabolism
Radiography
Radiology and Medical Imaging/Magnetic Resonance Imaging
Risk Factors
Schizophrenia
Schizophrenia - diagnostic imaging
Schizophrenia - genetics
Schizophrenia - metabolism
Schizophrenia - physiopathology
Single nucleotide polymorphisms
Studies
Twins
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000252