Cholinergic muscarinic M4 receptor gene polymorphisms: A potential risk factor and pharmacogenomic marker for schizophrenia

Abstract

Although schizophrenia is a widespread disorder of unknown aetiology, we have previously shown that muscarinic M4 receptor (CHRM4) expression is decreased in the hippocampus and caudate-putamen from subjects with the disorder, implicating the receptor in its pathophysiology. These findings led us to determine whether variation in the CHRM4 gene sequence was associated with an altered risk of schizophrenia by sequencing the CHRM4 gene from the brains of 76 people with the disorder and 74 people with no history of psychiatric disorders. In addition, because the CHRM4 is a potential target for antipsychotic drug development, we investigated whether variations in CHRM4 sequence were associated with final recorded doses of, and life-time exposure to, antipsychotic drugs. Gene sequencing identified two single nucleotide polymorphisms (SNPs; rs2067482 and rs72910092) in the CHRM4 gene. For rs2067482, our data suggested that both genotype (1341C/C; p = 0.05) and allele (C; p = 0.03) were associated with an increased risk of schizophrenia. In addition, there was a strong trend (p = 0.08) towards an association between CHRM4 sequence and increased lifetime exposure to antipsychotic drugs. Furthermore, there was a trend for people with the C allele to be prescribed benzodiazepines more frequently (p = 0.06) than those with the T allele. These data, albeit on small cohorts, are consistent with genetic variance at rs2067482 contributing to an altered risk of developing schizophrenia which requires more forceful pharmacotherapy to achieve a clinical response.

<p>Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia</p>

“…Surprisingly, the results of the allelic association of the rs2067482 polymorphism with the disease were opposite to the ones reported earlier: Scarr et al found allele C being associated with increased risk of schizophrenia. 16 In contrast, our study identified allele T having higher prevalence in schizophrenia patients ( Table 2). It is hard to explain such inconsistency but several reasons can be discussed.…”

“…7 Thereafter, they reported the synonymous polymorphism rs2067482 in CHRM4 to be associated with an increased risk of schizophrenia. 16 In the current study, we have confirmed an association of the rs2067482 variant with schizophrenia in 449 patients versus 134 healthy subjects. No difference in genotype was detected between patients with and without TD.…”

“…Secondly, no data is available concerning diagnostic subtyping and mental comorbidity of their patients which might affect the selection of the particular individual to the patient group. Moreover, many patients (exactly half of them in their 2013 study) 16 committed suicide, while none of the individuals in our study had suicidal tendencies, pointing out to different subtypes/severity of the disease. Thus, CHRM4 may be involved in anti-suicidal effects and not in schizophrenia in general.…”

“…In a previous study, Scarr et al made an attempt to determine whether variations in the CHRM4 gene sequence were associated with an altered risk of schizophrenia. 16 The CHRM4 gene was studied in 76 schizophrenia patients and 74 persons with no history of psychiatric disorders, and two genomic variants were identified, rs2067482 and rs72910092. Of these, only rs2067482, was found to be highly associated with schizophrenia, further linking CHRM4 to the disorder.…”

African-Specific Variability in the Acetylcholine Muscarinic Receptor M4: Association with Cocaine and Heroin Addiction

“…Nevertheless, as was pointed out by Rietschel et al, it was difficult to determine the susceptibility gene for schizophrenia based on the genetics data alone due to the strong LD in the region and the potential relevance of several genes in this region. Another study reported an association of a synonymous CHRM4 SNP, which was not analyzed in the current study, with schizophrenia, in a small Australian sample [41]. The implication for the results of the current study is that the CHRM4 SNP could be a marker in LD with a causative SNP in another gene in this region.…”