Association between PRODH and schizophrenia is not confirmed

Williams, Hywel; Williams, Nigel; Spurlock, Gillian; Norton, Nadine; Ivanov, Dobril; McCreadie, Robin G.; Preece, Anna; Sharkey, Val; Jones, Susan; Zammit, Stanley; Nikolov, Ivan; Kehaiov, I; Thapar, Anita; Murphy, K. C.; Kirov, George; Owen, Michael John

doi:10.1038/sj.mp.4001276

Cited by 52 publications

(37 citation statements)

References 6 publications

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“…This finding is not in conflict with the present data since three of these patients meet the DSM IIIR criteria for schizoaffective disorder. Molecular analysis, in accordance with two recent reports 19,20 revealed no association between common PRODH polymorphisms and schizophrenia. The frequency of the PRODH region deletion was recently set to 1 in 250 subjects (95% CI, 1 in 115 to 1 in 547 subjects) in the Japanese population, 21 indicating that the prevalence of this deletion is increased by 10-fold relative to 22q11 interstitial deletions.…”

Section: Discussionsupporting

confidence: 91%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P ¼ 0.02, Odds ratio ¼ 4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an An increased frequency of several psychotic disorders, such as children-onset schizophrenia, 1 schizophrenia, 2 and bipolar disorder, 3 has been observed in patients with the 22q11 deletion syndromes (22q11DS), 4 which include the DiGeorge syndrome (MIM 188400) and the velo-cardio-facial syndrome (MIM 192430). This has led to the hypothesis that sequence variations of one or several genes located within the 3 Mb region commonly deleted in most of the 22q11DS patients 5 might confer susceptibility for psychoses in the general population. In a previous study, we had identified in two schizophrenic relatives (diagnosed according to DSM III criteria) a 350 kb heterozygous deletion within the DiGeorge critical region (DGCR) removing entirely the proline dehydrogenase (PRODH) gene. This deletion was associated in patients with moderate hyperprolinemia. In addition, two heterozygous PRODH missense mutations (L441P and L289M) were detected in three of 63 schizophrenic patients but not in 68 controls, and these mutations were also associated with moderate hyperprolinemia. 6 Interestingly, we subsequently found the same PRODH deletion and the L441P substitution at the homozygous state in children suffering from a severe form of type I hyperprolinemia, a condition characterized by high plasma proline levels, seizures and mental retardation. 7 T...

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Section: Discussionsupporting

confidence: 91%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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“…Again, none were associated with schizophrenia. 141,142 Given the high power to replicate the previous findings, our data suggest that genetic variation in PRODH is unlikely to be associated with increased risk of schizophrenia, and that the first positive findings are most likely due to chance.…”

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confidence: 48%

“…Despite the fact that each sample had 495% power to replicate the findings, in none did we find evidence for association between either the putative PRODH risk haplotype or the mis-sense substitutions. 140,141 We also screened the complete cDNA sequence of PRODH and its pseudogene for novel sequence variants. Again, none were associated with schizophrenia.…”

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confidence: 99%

The molecular genetics of schizophrenia: new findings promise new insights

2003

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The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at Po0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia.

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“…353,354 However, the status of PRODH2 as a schizophrenia susceptibility gene remains equivocal, as association has not been replicated, either in a Chinese population (albeit only one of the positive SNPs 349 was studied), 355 or in a Japanese sample, 356 or in a large UK/Irish casecontrol group, which included early onset cases and several cases of VCFS with psychosis, along with 55 Bulgarian trios. 357 These authors subsequently sequenced the entire gene in 14 patients and failed to reveal any additional associated SNPs.…”

Section: G72 (And Daao)mentioning

confidence: 99%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. Molecular Psychiatry (2005) 10, 40-68.

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Association between PRODH and schizophrenia is not confirmed

Cited by 52 publications

References 6 publications

Hyperprolinemia is a risk factor for schizoaffective disorder

Hyperprolinemia is a risk factor for schizoaffective disorder

The molecular genetics of schizophrenia: new findings promise new insights

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

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