Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome

Abstract

Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, event-related oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7. Recently, we reported both linkage and association between polymorphisms in the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this study, we evaluated whether genetic variation in the CHRM2 gene is also a risk factor for the correlated clinical characteristics of alcoholism and depression. The CHRM2 gene contains a single coding exon and a large 5' untranslated region encoded by multiple exons that can be alternatively spliced. Families were recruited through an alcohol dependent proband, and multiplex pedigrees were selected for genetic analyses. We examined 11 single nucleotide polymorphisms (SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5) showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype (>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders.

Delta and theta oscillations as risk markers in adolescent offspring of alcoholics

“…Furthermore these identified genetic locations also have significant associations with the diagnoses of alcohol dependence Wang et al, 2004 ). In addition, recent studies suggested that GABRA2 is significantly associated with childhood conduct disorder symptoms as well as with marijuana dependence and illicit drug dependence ( Agrawal et al, 2006 ).…”

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

“…Specifically, Cannon et al (2006) reported that the distribution volume of the [ 18 F]FP-TZTP, a PET radioligand that is relatively selective for M2 receptors, was reduced in bipolar depressives relative to controls, although the sample size was too small to permit assessment of sex effects. In unipolar depression, Wang et al (2004) showed associations between genetic variation in the CHRM2 gene and depression arising in families with an alcohol-dependent proband, whereas Comings et al (2002) found that genetic variation in the 3 0 region of the CHRM2 gene (A/T 1890) was associated with MDD specifically in females. Taken together, these findings highlight the relevance of the muscarinic cholinergic system in depression and also appear complementary to the current report, as gender differences have been associated with both the genetic variation in the CHRM2 gene in MDD and now with the likelihood of experiencing an antidepressant response to scopolamine.…”

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…Those peaks harbor genes such as GABRA2, ADH (on chromosome 4) and CHRM2 and hTAS2R16 (on chromosome 7), which have subsequently found to be associated with risk for alcoholism Wang et al, 2004;Edenberg et al, 2006a;Hinrichs et al, 2006). We did not detect these peaks in our analyses.…”