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

Lucas Kempf, Kristin K. Nicodemus, Bhaskar Kolachana, Radhakrishna Vakkalanka, Beth A. Verchinski, Michael F. Egan, Richard E. Straub, Venkata A. Mattay, Joseph H. Callicott, Daniel R. Weinberger, Andreas Meyer-Lindenberg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1000252
JournalPLoS genetics
Volume4
Issue number11
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Kempf, L., Nicodemus, K. K., Kolachana, B., Vakkalanka, R., Verchinski, B. A., Egan, M. F., Straub, R. E., Mattay, V. A., Callicott, J. H., Weinberger, D. R., & Meyer-Lindenberg, A. (2008). Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. PLoS genetics, 4(11), [e1000252]. https://doi.org/10.1371/journal.pgen.1000252