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

Kempf L, Nicodemus KK, Kolachana B, Vakkalanka R, Verchinski BA, Egan MF, Straub RE, Mattay VA, Callicott JH, Weinberger DR, Meyer-Lindenberg A - PLoS Genet. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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Risk and Reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Decreases in grey matter volume for risk haplotype carrier in relationship to the reference haplotype, at p<0.001 uncorrected threshold. B) Extracted striatal cluster grey matter values plotted by haplotype. C) Areas of relatively decreased BOLD signal for risk haplotype vs. reference effect on the working memory network in normal subjects in the working memory network visualized at uncorrected p<0.001 (VLPFC) k = 13 Z = 3.39, p<0.045 small volume corrected for VLPFC (45, −45, 42) k = 31 Z = 3.81, p<0.043 small volume corrected BA 40. Df) Area of relatively increased and E) decreased striatal connectivity for the risk haplotype at uncorrected p<0.05. Statistical mappings are overlaid on a single subject T1 images. Statistical results after multiple comparison correction shown in Tables S1, S2 and S3.
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pgen-1000252-g002: Risk and Reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Decreases in grey matter volume for risk haplotype carrier in relationship to the reference haplotype, at p<0.001 uncorrected threshold. B) Extracted striatal cluster grey matter values plotted by haplotype. C) Areas of relatively decreased BOLD signal for risk haplotype vs. reference effect on the working memory network in normal subjects in the working memory network visualized at uncorrected p<0.001 (VLPFC) k = 13 Z = 3.39, p<0.045 small volume corrected for VLPFC (45, −45, 42) k = 31 Z = 3.81, p<0.043 small volume corrected BA 40. Df) Area of relatively increased and E) decreased striatal connectivity for the risk haplotype at uncorrected p<0.05. Statistical mappings are overlaid on a single subject T1 images. Statistical results after multiple comparison correction shown in Tables S1, S2 and S3.

Mentions: The functional risk-associated haplotype (GCC) was associated with reduced regional gray matter volume in the neostriatum in the normal control sample (21, 22, −6, z = 4.92, P<0.05 whole brain corrected false discovery rate (FDR) (Figure 2 A and B). In a post hoc exploratory analysis, the protective haplotype (ACT) revealed a non significant trend towards gray matter volume increase in the frontal lobes (−21, 53, 8, z = 3.97, P<0.001 uncorrected) (Figure 2 A and B) and occipital lobes (21,−85, 17, z = 4.26, P<0.001 uncorrected) (Table S1).


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

Kempf L, Nicodemus KK, Kolachana B, Vakkalanka R, Verchinski BA, Egan MF, Straub RE, Mattay VA, Callicott JH, Weinberger DR, Meyer-Lindenberg A - PLoS Genet. (2008)

Risk and Reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Decreases in grey matter volume for risk haplotype carrier in relationship to the reference haplotype, at p<0.001 uncorrected threshold. B) Extracted striatal cluster grey matter values plotted by haplotype. C) Areas of relatively decreased BOLD signal for risk haplotype vs. reference effect on the working memory network in normal subjects in the working memory network visualized at uncorrected p<0.001 (VLPFC) k = 13 Z = 3.39, p<0.045 small volume corrected for VLPFC (45, −45, 42) k = 31 Z = 3.81, p<0.043 small volume corrected BA 40. Df) Area of relatively increased and E) decreased striatal connectivity for the risk haplotype at uncorrected p<0.05. Statistical mappings are overlaid on a single subject T1 images. Statistical results after multiple comparison correction shown in Tables S1, S2 and S3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2573019&req=5

pgen-1000252-g002: Risk and Reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Decreases in grey matter volume for risk haplotype carrier in relationship to the reference haplotype, at p<0.001 uncorrected threshold. B) Extracted striatal cluster grey matter values plotted by haplotype. C) Areas of relatively decreased BOLD signal for risk haplotype vs. reference effect on the working memory network in normal subjects in the working memory network visualized at uncorrected p<0.001 (VLPFC) k = 13 Z = 3.39, p<0.045 small volume corrected for VLPFC (45, −45, 42) k = 31 Z = 3.81, p<0.043 small volume corrected BA 40. Df) Area of relatively increased and E) decreased striatal connectivity for the risk haplotype at uncorrected p<0.05. Statistical mappings are overlaid on a single subject T1 images. Statistical results after multiple comparison correction shown in Tables S1, S2 and S3.
Mentions: The functional risk-associated haplotype (GCC) was associated with reduced regional gray matter volume in the neostriatum in the normal control sample (21, 22, −6, z = 4.92, P<0.05 whole brain corrected false discovery rate (FDR) (Figure 2 A and B). In a post hoc exploratory analysis, the protective haplotype (ACT) revealed a non significant trend towards gray matter volume increase in the frontal lobes (−21, 53, 8, z = 3.97, P<0.001 uncorrected) (Figure 2 A and B) and occipital lobes (21,−85, 17, z = 4.26, P<0.001 uncorrected) (Table S1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus