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Human Molecular Genetics Advance Access published online on June 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh194
© 2004 by Oxford University Press
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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. Wang 1, Anthony L. Hinrichs 1, Heather Stock 1, John Budde 1, Rebecca Allen 1, Sarah Bertelsen 1, Jennifer M. Kwon 1, William Wu 1, Danielle M. Dick 1, John Rice 1, Kevin Jones 2, John I. Nurnberger Jr3, Jay Tischfield 4, Bernice Porjesz 2, Howard J. Edenberg 3, Victor Hesselbrock 5, Ray Crowe 6, Mark Schuckit 7, Henri Begleiter 2, Theodore Reich 1, Alison M. Goate 8*, Laura J. Bierut 1

1 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110
2 SUNY Health Science Center at Brooklyn, Brooklyn, NY, 11203
3 Indiana University School of Medicine, Indianapolis, IN, 46202
4 Rutgers University, Piscataway, NJ, 08854
5 University of Connecticut School of Medicine, Farmington, CT, 06030
6 University of Iowa School of Medicine, Iowa City, IA, 52242
7 University of California at San Diego School of Medicine, La Jolla, CA, 92161
8 Dept. of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110

* To whom correspondence should be addressed. E-mail: goate{at}icarus.wustl.edu.


  Abstract

Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, Event Related Oscillations, 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 Event-Related Oscillations. 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 eleven 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 value range 0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (p=0.004 and p=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.


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