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, Anthony L. Hinrichs, Heather Stock, John Budde, Rebecca Allen, Sarah Bertelsen, Jennifer M. Kwon, William Wu, Danielle M. Dick, John Rice, Kevin Jones, John Nurnberger, Jay Tischfield, Bernice Porjesz, Howard Edenberg, Victor Hesselbrock, Ray Crowe, Mark Schuckit, Henri Begleiter, Theodore ReichAlison M. Goate, Laura J. Bierut

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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.

Original languageEnglish
Pages (from-to)1903-1911
Number of pages9
JournalHuman Molecular Genetics
Volume13
Issue number17
DOIs
StatePublished - Sep 1 2004

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Muscarinic M2 Receptors
Muscarinic Receptors
Depressive Disorder
Alcoholism
Introns
Haplotypes
Single Nucleotide Polymorphism
Pedigree
Genes
Exons
Alcohols
Endophenotypes
Chromosomes, Human, Pair 7
5' Untranslated Regions
Psychiatry
Depression
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Evidence of common and specific genetic effects : Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. / Wang, Jen C.; Hinrichs, Anthony L.; Stock, Heather; Budde, John; Allen, Rebecca; Bertelsen, Sarah; Kwon, Jennifer M.; Wu, William; Dick, Danielle M.; Rice, John; Jones, Kevin; Nurnberger, John; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard; Hesselbrock, Victor; Crowe, Ray; Schuckit, Mark; Begleiter, Henri; Reich, Theodore; Goate, Alison M.; Bierut, Laura J.

In: Human Molecular Genetics, Vol. 13, No. 17, 01.09.2004, p. 1903-1911.

Research output: Contribution to journalArticle

Wang, JC, Hinrichs, AL, Stock, H, Budde, J, Allen, R, Bertelsen, S, Kwon, JM, Wu, W, Dick, DM, Rice, J, Jones, K, Nurnberger, J, Tischfield, J, Porjesz, B, Edenberg, H, Hesselbrock, V, Crowe, R, Schuckit, M, Begleiter, H, Reich, T, Goate, AM & Bierut, LJ 2004, 'Evidence of common and specific genetic effects: Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome', Human Molecular Genetics, vol. 13, no. 17, pp. 1903-1911. https://doi.org/10.1093/hmg/ddh194
Wang, Jen C. ; Hinrichs, Anthony L. ; Stock, Heather ; Budde, John ; Allen, Rebecca ; Bertelsen, Sarah ; Kwon, Jennifer M. ; Wu, William ; Dick, Danielle M. ; Rice, John ; Jones, Kevin ; Nurnberger, John ; Tischfield, Jay ; Porjesz, Bernice ; Edenberg, Howard ; Hesselbrock, Victor ; Crowe, Ray ; Schuckit, Mark ; Begleiter, Henri ; Reich, Theodore ; Goate, Alison M. ; Bierut, Laura J. / Evidence of common and specific genetic effects : Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 17. pp. 1903-1911.
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AU - Hinrichs, Anthony L.

AU - Stock, Heather

AU - Budde, John

AU - Allen, Rebecca

AU - Bertelsen, Sarah

AU - Kwon, Jennifer M.

AU - Wu, William

AU - Dick, Danielle M.

AU - Rice, John

AU - Jones, Kevin

AU - Nurnberger, John

AU - Tischfield, Jay

AU - Porjesz, Bernice

AU - Edenberg, Howard

AU - Hesselbrock, Victor

AU - Crowe, Ray

AU - Schuckit, Mark

AU - Begleiter, Henri

AU - Reich, Theodore

AU - Goate, Alison M.

AU - Bierut, Laura J.

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N2 - 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.

AB - 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.

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