Human Molecular Genetics Advance Access published online on July 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi244
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1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT; VA Connecticut Healthcare System, West Haven Campus, CT
* To whom correspondence should be addressed. Cholinergic muscarinic 2 receptor (CHRM2) is implicated in memory and cognition, functions impaired in many neuropsychiatric disorders. Wang et al. (2004) reported that variation in CHRM2 gene predisposed to alcohol dependence (AD) and major depressive syndrome. We examined the relationships between variation in CHRM2 and AD, drug dependence (DD) and affective disorders, using a novel extended case-control structured association (SA) method. Six markers at CHRM2 and 38 ancestry-informative markers (AIMs) were genotyped in a sample of 871 subjects, including 333 healthy controls [287 European-Americans (EAs) and 46 African-Americans (AAs)] and 538 AD and/or DD subjects (415 with AD and 346 with DD; 382 EAs and 156 AAs). The same CHRM2 markers were genotyped in a sample of 137 EA subjects with affective disorders. All of the six markers were in HWE in controls, but SNP3 (rs1824024) was in Hardy-Weinberg Disequilibrium (HWD) in the AD and DD groups. Using conventional case-control comparisons, some markers were nominally significantly or suggestively associated with phenotypes before or after controlling for population stratification and admixture effects, but these associations were not significant after multiple test correction. However, regression analysis identified specific alleles, genotypes, haplotypes, and diplotypes that were significantly associated with risk for each disorder. We conclude that variation in CHRM2 predisposes to AD, DD, and affective disorders. One haplotype block within the 5'-UTR of CHRM2 may be more important for development of these disorders than other regions. Interaction between two specific alleles within this block and interaction between two specific diplotypes covering this block multiplicatively increased risk for AD and DD, but the latter antagonistically increased risk for affective disorders. Consequently, a specific diplotype might inversely affect risk for AD and DD, and risk for affective disorders.
Received May 30, 2005
Revised June 24, 2005
Accepted July 1, 2005
Article
CHRM2 gene predisposes to alcohol dependence, drug dependence, and affective disorders: results from an extended case-control structured association study
2 University of Connecticut School of Medicine, Alcohol Research Center, Department of Psychiatry, Farmington, CT
3 Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
Joel Gelernter, E-mail: joel.gelernter{at}yale.edu
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