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Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder.

ABSTRACT: Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. A single nucleotide polymorphism (SNP) in each of six genes, TDO2, HM74, HM74A, MCHR1, MCHR2 and MC5R, was tested for association with phenotype (475 Caucasians, 88 African Americans with schizophrenia; 97 Caucasians, 3 African Americans with bipolar disorder; 191 Caucasian, 49 African American controls). An A allele in HM74 was significantly associated with schizophrenia and with schizophrenia plus bipolar disorder combined, odds ratios (OR) of 1.48, p=0.011 and 1.50, p=0.007, respectively. Augmentation of disease risk was found for the complex genotype HM74[A,any]+MCHR1[T,any]+MCHR2[C,any] which conferred an OR maximal for the combined diagnostic category of schizophrenia plus bipolar disorder (1.70, p=0.003), carried by 30% of the cases. TDO2[CC]+MC5R[G, any]+MCHR2[GC] conferred an OR maximal for schizophrenia alone (4.84, p=0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melanotropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.

SUBMITTER: Miller CL

PROVIDER: S-EPMC2855687 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder.

Miller Christine L CL Murakami Peter P Ruczinski Ingo I Ross Randal G RG Sinkus Melissa M Sullivan Bernadette B Leonard Sherry S

Schizophrenia research 20090606 2-3

Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal mod ...[more]

PMID: 19502010

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Project description:Schizophrenia (SCZ) and bipolar disorder (BD) are associated with immunological dysfunctions that have been hypothesized to lead to clinical symptomatology in particular through kynurenine pathway abnormalities. The aim of this study was thus to investigate the impact of serum kynurenine metabolite levels on diagnosis, clinical state, symptom severity and clinical course in a large French transdiagnostic cohort of SCZ and BD patients. Four patient groups (total n = 507) were included in a cross-sectional observational study: 1) hospitalized acute bipolar patients (n = 205); 2) stable bipolar outpatients (n = 116); 3) hospitalized acute schizophrenia patients (n = 111) and 4) stable schizophrenia outpatients (n = 75), in addition to healthy controls (HC) (n = 185). The quantitative determination of serum kynurenine metabolites was performed using liquid chromatography-tandem mass spectrometry. Kynurenine levels were lower in all patients combined compared to HC while ANCOVA analyses did not reveal inter-diagnostic difference between SCZ and BD. Interestingly, hospitalized patients of both diagnostic groups combined displayed significantly lower kynurenine levels than stabilized outpatients. Psychotic symptoms were associated with lower quinaldic acid (F = 9.18, p=<.001), which is KAT-driven, whereas a longer duration of illness contributed to abnormalities in tryptophan (F = 5.41, p = .023), kynurenine (F = 16.93, p=<.001), xanthurenic acid (F = 9.34, p = .002), quinolinic acid (F = 9.18, p = .003) and picolinic acid (F = 4.15, p = .043), metabolized through the KMO-branch. These data confirm illness state rather than diagnosis to drive KP alterations in SCZ and BD. Lower levels of KP metabolites can thus be viewed as a transdiagnostic feature of SCZ and BD, independently associated with acute symptomatology and a longer duration of illness. Quinaldic acid has seldomly been investigated by previous studies and appears an important state marker in SCZ and BD. As serum samples are used in this study, it is not possible to extrapolate these findings to the brain.

Project description:IntroductionThe kynurenine pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of the kynurenine pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD.MethodsPubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies until April 2022 that assessed kynurenine metabolites, namely, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), and 3- hydroxykynurenine (3-HK) in SZ, BD, or MDD subjects compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected when comparing the standardized mean differences (SMD) between two groups.ResultsThere were 23 articles that met the inclusion criteria (k=8, k=8, k=11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased [SMD=2.64, confidence interval (CI) =1.16 to 4.13, p=0.0005, I2=96%, k=6, n=384 subjects]. TRP (k=5) and KYN (k=4) did not differ significantly. In BD, TRP levels (k=7) did not differ significantly. The level of KA was increased in MDD (k=2), but the small number of studies made not possible for statistical significance evaluation. Finally, in MDD, although some studies tended to have an increased level of KYN in those with remission versus decreased levels in those with current depression, no significant difference was found in any of the kynurenine metabolite levels. Similarly, there was an increased level of QA (k=2) but the number of studies (k= 2) was small.ConclusionKA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. There may be alterations in this pathway based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

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Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder.

Publications

Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder.

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