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 Mattay, Joseph H. Callicott, Daniel 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
Externally publishedYes

Fingerprint

Corpus Striatum
Proline Oxidase
Schizophrenia
polymorphism
genetic polymorphism
connectivity
Haplotypes
proline
haplotypes
22q11 Deletion Syndrome
Multimodal Imaging
DiGeorge Syndrome
genetic variation
allele
pathophysiology
Prefrontal Cortex
linkage (genetics)
Alleles
schizophrenia
image analysis

ASJC Scopus subject areas

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

Cite this

Kempf, L., Nicodemus, K. K., Kolachana, B., Vakkalanka, R., Verchinski, B. A., Egan, M. F., ... 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

Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. / Kempf, Lucas; Nicodemus, Kristin K.; Kolachana, Bhaskar; Vakkalanka, Radhakrishna; Verchinski, Beth A.; Egan, Michael F.; Straub, Richard E.; Mattay, Venkata; Callicott, Joseph H.; Weinberger, Daniel; Meyer-Lindenberg, Andreas.

In: PLoS Genetics, Vol. 4, No. 11, e1000252, 11.2008.

Research output: Contribution to journalArticle

Kempf, L, Nicodemus, KK, Kolachana, B, Vakkalanka, R, Verchinski, BA, Egan, MF, Straub, RE, Mattay, V, Callicott, JH, Weinberger, D & Meyer-Lindenberg, A 2008, 'Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function', PLoS Genetics, vol. 4, no. 11, e1000252. https://doi.org/10.1371/journal.pgen.1000252
Kempf, Lucas ; Nicodemus, Kristin K. ; Kolachana, Bhaskar ; Vakkalanka, Radhakrishna ; Verchinski, Beth A. ; Egan, Michael F. ; Straub, Richard E. ; Mattay, Venkata ; Callicott, Joseph H. ; Weinberger, Daniel ; Meyer-Lindenberg, Andreas. / Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. In: PLoS Genetics. 2008 ; Vol. 4, No. 11.
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