| 1 | Schizophr. Res. 2009 Sep 113: 259-67 |
|---|---|
| PMID | 19502010 |
| Title | 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. |
| SCZ Keywords | schizophrenia |
| 2 | Psychiatr. Genet. 2012 Apr 22: 62-9 |
| PMID | 22081064 |
| Title | The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case-control sample. |
| Abstract | The MCHR1 gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR1 gene and schizophrenia, based on analyses of a larger sample and an increased number of single nucleotide polymorphisms (SNPs) than used in the previous study. Eighteen SNPs in the MCHR1 gene region were genotyped in a Caucasian case-control sample from Denmark consisting of 390 individuals with schizophrenia and 814 control individuals. Sex-specific analysis and analysis of association with antipsychotic treatment were performed. Five SNPs in the proximal region of MCHR1 were significantly associated with schizophrenia. The associations seemed to be sex specific, predominantly seen in men where one SNP (rs133073) remained significant (P=0.003) after correction for multiple testing. When combining the P values in the proximal region of MCHR1, the region-wise P value was low (P=0.009) supporting that variations in this part of the gene is associated with schizophrenia. Furthermore, the association was stronger in patients responding to conventional and atypical antipsychotic medication except clozapine. Our results suggest that MCHR1 may influence schizophrenia susceptibility, in particular among men and patients responding to conventional (nonclozapine) treatment. |
| SCZ Keywords | schizophrenia |