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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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Protective and reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Increases in grey matter volume for protective haplotype carriers in relationship to reference haplotype at p<0.001 uncorrected threshold. B) Extracted values of cluster grey matter for left frontal lobe at threshold of p<0.001 as a function of protective haplotype. C) Relatively decreased BOLD signal of early sensory processing stream for protective haplotype carriers on the working memory network in normal subjects at FDR<0.047 full brain corrected. D) Decreased BOLD signal for protective haplotype carriers in relationship to reference haplotype, at p<0.05 uncorrected threshold within Caudate and Putamen as defined by the Wake Forest University brain atlas. Areas of relatively E) increased and F) decreased connectivity for protective haplotype effect at uncorrected threshold of 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-g003: Protective and reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Increases in grey matter volume for protective haplotype carriers in relationship to reference haplotype at p<0.001 uncorrected threshold. B) Extracted values of cluster grey matter for left frontal lobe at threshold of p<0.001 as a function of protective haplotype. C) Relatively decreased BOLD signal of early sensory processing stream for protective haplotype carriers on the working memory network in normal subjects at FDR<0.047 full brain corrected. D) Decreased BOLD signal for protective haplotype carriers in relationship to reference haplotype, at p<0.05 uncorrected threshold within Caudate and Putamen as defined by the Wake Forest University brain atlas. Areas of relatively E) increased and F) decreased connectivity for protective haplotype effect at uncorrected threshold of 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: To further characterize these findings functionally, we analyzed the effect of the risk haplotype during working memory in the normal sample. Network activation patterns differed, with reduced blood oxygenation level-dependent (BOLD) signal in ventral lateral prefrontal cortex (VLPFC, z = 3.18, p<0.05 corrected) and parietal lobes (Brodmann area (BA) 40, z = 3.52, p<0.05 corrected) (Figure 2C) relative to the reference haplotype. (Table S2) Functional connectivity for the bilateral striatal seed regions showed trends for increased dorsal lateral prefrontal-striatal functional connectivity (Figure 2D) for the risk haplotype carriers. (Table S3) In contrast, the protective haplotype carriers had decreased BOLD in bilateral striatum compared to reference (−22, 0, 12, z = 3.23, p = 0.05 corrected) (Figure 3D), decreased recruitment of areas of early visual processing (BA 18, fusiform gyrus, BA6, BA19, z = 3.92, p<0.05 whole brain corrected) (Figure 3C) (Table S4) and a decreased striatal-frontal functional connectivity, z = 3.75, p<0.037 corrected for region of interest (ROI) (Figure 3E and F) (Table S3). Performance was not significantly different between haplotype groups (Table S5). Post hoc analysis including performance as a nuisance covariate had similar activation patterns.


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)

Protective and reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Increases in grey matter volume for protective haplotype carriers in relationship to reference haplotype at p<0.001 uncorrected threshold. B) Extracted values of cluster grey matter for left frontal lobe at threshold of p<0.001 as a function of protective haplotype. C) Relatively decreased BOLD signal of early sensory processing stream for protective haplotype carriers on the working memory network in normal subjects at FDR<0.047 full brain corrected. D) Decreased BOLD signal for protective haplotype carriers in relationship to reference haplotype, at p<0.05 uncorrected threshold within Caudate and Putamen as defined by the Wake Forest University brain atlas. Areas of relatively E) increased and F) decreased connectivity for protective haplotype effect at uncorrected threshold of 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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2573019&req=5

pgen-1000252-g003: Protective and reference haplotypes: multimodal imaging results (see supplemental tables for results surviving multiple comparison correction).A) Increases in grey matter volume for protective haplotype carriers in relationship to reference haplotype at p<0.001 uncorrected threshold. B) Extracted values of cluster grey matter for left frontal lobe at threshold of p<0.001 as a function of protective haplotype. C) Relatively decreased BOLD signal of early sensory processing stream for protective haplotype carriers on the working memory network in normal subjects at FDR<0.047 full brain corrected. D) Decreased BOLD signal for protective haplotype carriers in relationship to reference haplotype, at p<0.05 uncorrected threshold within Caudate and Putamen as defined by the Wake Forest University brain atlas. Areas of relatively E) increased and F) decreased connectivity for protective haplotype effect at uncorrected threshold of 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: To further characterize these findings functionally, we analyzed the effect of the risk haplotype during working memory in the normal sample. Network activation patterns differed, with reduced blood oxygenation level-dependent (BOLD) signal in ventral lateral prefrontal cortex (VLPFC, z = 3.18, p<0.05 corrected) and parietal lobes (Brodmann area (BA) 40, z = 3.52, p<0.05 corrected) (Figure 2C) relative to the reference haplotype. (Table S2) Functional connectivity for the bilateral striatal seed regions showed trends for increased dorsal lateral prefrontal-striatal functional connectivity (Figure 2D) for the risk haplotype carriers. (Table S3) In contrast, the protective haplotype carriers had decreased BOLD in bilateral striatum compared to reference (−22, 0, 12, z = 3.23, p = 0.05 corrected) (Figure 3D), decreased recruitment of areas of early visual processing (BA 18, fusiform gyrus, BA6, BA19, z = 3.92, p<0.05 whole brain corrected) (Figure 3C) (Table S4) and a decreased striatal-frontal functional connectivity, z = 3.75, p<0.037 corrected for region of interest (ROI) (Figure 3E and F) (Table S3). Performance was not significantly different between haplotype groups (Table S5). Post hoc analysis including performance as a nuisance covariate had similar activation patterns.

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