TY - JOUR
T1 - Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function
AU - Kempf, Lucas
AU - Nicodemus, Kristin K.
AU - Kolachana, Bhaskar
AU - Vakkalanka, Radhakrishna
AU - Verchinski, Beth A.
AU - Egan, Michael F.
AU - Straub, Richard E.
AU - Mattay, Venkata A.
AU - Callicott, Joseph H.
AU - Weinberger, Daniel R.
AU - Meyer-Lindenberg, Andreas
PY - 2008/11
Y1 - 2008/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=57149120578&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57149120578&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1000252
DO - 10.1371/journal.pgen.1000252
M3 - Article
C2 - 18989458
AN - SCOPUS:57149120578
SN - 1553-7390
VL - 4
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1000252
ER -