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Human Molecular Genetics Advance Access originally published online on June 30, 2004
Human Molecular Genetics 2004 13(17):1903-1911; doi:10.1093/hmg/ddh194
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Human Molecular Genetics, Vol. 13, No. 17 © Oxford University Press 2004; all rights reserved

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

Jen C. Wang1, Anthony L. Hinrichs1, Heather Stock1, John Budde1, Rebecca Allen1, Sarah Bertelsen1, Jennifer M. Kwon1, William Wu1, Danielle M. Dick1, John Rice1, Kevin Jones2, John I. Nurnberger, Jr3, Jay Tischfield4, Bernice Porjesz2, Howard J. Edenberg3, Victor Hesselbrock5, Ray Crowe6, Mark Schuckit7, Henri Begleiter2, Theodore Reich1, Alison M. Goate1,* and Laura J. Bierut1

1Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA, 2SUNY Health Science Center at Brooklyn, Brooklyn, NY 11203, USA, 3Indiana University School of Medicine, Indianapolis, IN 46202, USA, 4Rutgers University, Piscataway, NJ 08854, USA, 5University of Connecticut School of Medicine, Farmington, CT 06030, USA, 6University of Iowa School of Medicine, Iowa City, IA 52242, USA and 7University of California at San Diego School of Medicine, La Jolla, CA 92161, USA

Received April 23, 2004; Accepted June 15, 2004

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.

* To whom correspondence should be addressed at: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA. Tel: +1 3143628691; Fax: +1 3147472983; Email: goate{at}icarus.wustl.edu


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