Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.
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.
Wang
Jen C
JC
Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
Hinrichs
Anthony L
AL
Stock
Heather
H
Budde
John
J
Allen
Rebecca
R
Bertelsen
Sarah
S
Kwon
Jennifer M
JM
Wu
William
W
Dick
Danielle M
DM
Rice
John
J
Jones
Kevin
K
Nurnberger
John I
JI
Tischfield
Jay
J
Porjesz
Bernice
B
Edenberg
Howard J
HJ
Hesselbrock
Victor
V
Crowe
Ray
R
Schuckit
Mark
M
Begleiter
Henri
H
Reich
Theodore
T
Goate
Alison M
AM
Bierut
Laura J
LJ
D000437:Alcoholism / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D040461:Gene Components; D008040:Genetic Linkage; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043585:Receptor, Muscarinic M2 / Q000235:genetics*; D017422:Sequence Analysis, DNA
C487078:CHRM2 protein, human; D043585:Receptor, Muscarinic M2