TY - JOUR
T1 - Evidence of common and specific genetic effects
T2 - Association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome
AU - Wang, Jen C.
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 I.
AU - Tischfield, Jay
AU - Porjesz, Bernice
AU - Edenberg, Howard J.
AU - Hesselbrock, Victor
AU - Crowe, Ray
AU - Schuckit, Mark
AU - Begleiter, Henri
AU - Reich, Theodore
AU - Goate, Alison M.
AU - Bierut, Laura J.
PY - 2004/9/1
Y1 - 2004/9/1
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.
UR - http://www.scopus.com/inward/record.url?scp=4544236290&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddh194
DO - 10.1093/hmg/ddh194
M3 - Article
C2 - 15229186
AN - SCOPUS:4544236290
SN - 0964-6906
VL - 13
SP - 1903
EP - 1911
JO - Human molecular genetics
JF - Human molecular genetics
IS - 17
ER -