Association of Muscarinic M1 Receptor Genetic Polymorphisms with Psychiatric Symptoms and Cognitive Function in Schizophrenic Patients

Abstract

Objective: The cholinergic system is important in the search for the pathophysiology of schizophrenia due to its role in cognitive function, interaction with the dopamine system in brain regions relevant to schizophrenia, side effects of antipsychotic medication and potential antipsychotic effect of muscarinic receptor antagonists. This study investigated the association of type I muscarinic receptor (CHRM1) genetic polymorphisms with the clinical characteristics of chronic schizophrenic inpatients. Methods: We determined the genotype of CHRM1 genetic polymorphisms in 243 schizophrenic patients hospitalized in chronic care wards. Psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS), and cognitive function was assessed using the Folstein Mini-Mental Status Examination (MMSE) test. Sixty of the 243 subjects also completed the Wisconsin Card Sorting Test (WCST). Results: There was a significant difference in the number of correct responses and the percentage of perseverative errors in the WCST in the CHRM1 C267A genotype group of schizophrenia patients. There was no significant association between age at onset, chlorpromazine equivalents, BPRS scores, MMSE or schizophrenia per se in patients with the CHRM1 C267A genotype. The full exon of the CHRM1 gene was screened out with single-strand conformation polymorphism, and 2 single nucleotide polymorphisms (C267A and C1353T) were identified in our patients and control subjects. These 2 single nucleotide polymorphisms were linked together without exception. Conclusion: This study demonstrated that in schizophrenic patients, the heterozygote group of CHRM1 C267A polymorphism (267C/A) had more correct responses and less perseverative errors on the WCST performance than the 267C/C homozygote group, implicating that this polymorphism may be related to prefrontal cortical function. Our results also suggested that the C267A polymorphism plays no major role in the susceptibility to and clinical manifestations of schizophrenia.

Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype

“…Importantly, while we detected only 5 of the 11 CHRM1 SNPs previously reported, 30 the SNPs we failed to detect occur mainly in African Americans and Hispanic populations, 30 which are not represented in our cohorts. Moreover, we have confirmed a previous finding 16 of complete linkage between the c.267C > A and c.1353C > T SNPs. Although our data identify possible changes in SNP frequencies in schizophrenia, there is the potential for a type I error in our study due to the relatively small sample size.…”

“…12 Furthermore, the availability of more selective tools has made it possible to show that it is the cortical CHRM1 that is selectively decreased in schizophrenia. [13][14][15] Moreover, a recent finding that the c.267C/C genotype at the c.267A/C polymorphism in the CHRM1 is associated with more severe cognitive deficits in schizophrenia, 16 suggests that variation in CHRM1 gene sequence and/or expression might be associated with a key symptom of the disorder. Together, these data suggest that abnormalities in CHRMs may significantly contribute to the pathology of the disorder.…”

Towards a muscarinic hypothesis of schizophrenia

“…199 A polymorphism of the M 1 muscarinic receptor gene was associated with a better score on the Wisconsin Card Sorting Test in schizophrenia. 200 No other genetic studies have been reported on the muscarinic cholinergic system in schizophrenia so far.…”

Polymorphisms in the Muscarinic Receptor 1 Gene Confer Susceptibility to Asthma in Japanese Subjects

“…Genomic DNA from Japanese subjects was genotyped for ϩ267A Ͼ C (rs2067477) and ϩ1353C Ͼ T (rs2067480), because an association of these polymorphisms at the muscarinic M1 receptor gene with cognitive function in schizophrenic patients has been reported (19). We selected an additional seven SNPs for genotyping based on the frequency and location of SNPs and the linkage disequilibrium (LD) structure in and around the CHRM1 gene.…”