1Mol. Psychiatry 2012 Sep 17: 906-17
TitleAssociation between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe.
AbstractRecent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11?540; P=3.89 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23?206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.
SCZ Keywordsschizophrenia
2Schizophr. Res. 2013 May 146: 279-84
TitleCholinergic muscarinic M4 receptor gene polymorphisms: a potential risk factor and pharmacogenomic marker for schizophrenia.
AbstractAlthough 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.
SCZ Keywordsschizophrenia
3Curr. Mol. Med. 2015 -1 15: 253-64
TitlePossible involvement of muscarinic receptors in psychiatric disorders: a focus on schizophrenia and mood disorders.
AbstractA considerable body of data supports a role for the central cholinergic system in the aetiologies of schizophrenia and mood disorders. There have been breakthroughs in gaining structural data on muscarinic receptors (CHRMs), understanding their role in CNS functioning and in synthesising drugs that can specifically target each of the 5 CHRMs. This means it is opportune to consider the role of specific CHRMs in the pathophysiologies of schizophrenia and mood disorders. This review will focus on data suggesting changes in levels of CHRM1 and CHRM4 implicate these receptors in the pathophysiology of schizophrenia whereas data suggest a role for CHRM2 in mood disorders. There will be a selected reference to recent developments in understanding the roles of CHRM1, 2 and 4 in CNS function and how these predict mechanisms by which these receptors could induce the symptoms prevalent in schizophrenia and mood disorders. Finally, there will be comments on the potential advantages and problems in targeting CHRM1 and CHRM4 to treat the symptoms of schizophrenia and CHRM2 to treat the symptom of depression.
SCZ Keywordsschizophrenia
4Curr. Pharm. Des. 2016 -1 22: 2124-33
TitleThe Cholinergic System: An Emerging Drug Target for Schizophrenia.
AbstractCognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms.
We review the literature supporting the dysfunction of the cholinergic system in schizophrenia, discuss the preclinical and clinical data showing that modulating the cholinergic system could improve the symptoms of schizophrenia and review the main pharmacological strategies being investigated to treat cholinergic dysfunction in schizophrenia.
Post-mortem and neuroimaging studies suggest there are widespread reductions in cholinergic receptor signalling in the cortex as well as subcortical regions, such as the hippocampus and striatum, in individuals with schizophrenia. Potential cholinergic drug targets are being pursued to increase receptor function. These include inhibiting the activity of the enzyme acetylcholinesterase to increase synaptic acetylcholine levels, and increasing the nicotinic receptor and muscarinic receptor activity with agonists or positive allosteric modulators.
Amongst the most promising drug targets for treating schizophrenia are the ?7 nicotinic receptor and the CHRM1 and CHRM4 muscarinic receptors. The recent development of allosteric modulators that selectively target these receptors offers the potential to more effectively treat the symptoms of schizophrenia.
SCZ Keywordsschizophrenia