Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior.
paper
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- Authors
- Schumann, Gunter; Johann, Monika; Frank, Josef; Preuss, Ulrich; Dahmen, Norbert; Laucht, Manfred; Rietschel, Marcella; Rujescu, Dan; Lourdusamy, Anbarasu; Clarke, Toni-Kim; Krause, Kristina; Dyer, Anne; Depner, Martin; Wellek, Stefan; Treutlein, Jens; Szegedi, Armin; Giegling, Ina; Cichon, Sven; Blomeyer, Dorothea; Heinz, Andreas; Heath, Simon; Lathrop, Mark; Wodarz, Norbert; Soyka, Michael; Spanagel, Rainer; Mann, Karl
- Year
- 2008
- Journal
- Archives of general psychiatry
- PMID
- 18606955
- DOI
- 10.1001/archpsyc.65.7.826
CONTEXT: Glutamatergic neurotransmission is implicated in alcohol-drinking behavior in animal models. OBJECTIVE: To investigate whether genetic variations in glutamatergic neurotransmission genes, which are known to alter alcohol effects in rodents, contribute to the genetic basis of alcoholism in humans. DESIGN: Association analysis of alcohol dependence and haplotype-tagging single nucleotide polymorphisms (SNPs) covering 10 glutamatergic genes. Resequencing of functional domains of these genes identified 204 SNPs. Haplotypes with a frequency of 5% or greater could be discriminated by 21 haplotype-tagging SNPs analyzed for association in 2 independent samples of alcohol-dependent adult patients and controls as well as adolescent trios. SETTING: Four university medical centers in the south of Germany. PARTICIPANTS: One thousand three hundred thirty-seven patients and 1555 controls (study 1: 544 patients, 553 controls; study 2: 793 patients, 1002 controls). One hundred forty-four trios of 15-year-old adolescents assessed for risky drinking behavior. MAIN OUTCOME MEASURES: Genotype profiles for GLAST; N-methyl-d-aspartate-receptor subunits NR1, NR2A, and NR2B; MGLUR5; NNOS; PRKG2; CAMK4; the regulatory subunit of PI3K; and CREB were analyzed for association with alcohol dependence using multivariate statistical analysis. Risky adolescent drinking was tested using the transmission disequilibrium test. RESULTS: Analysis of study 1 revealed that NR2A and MGLUR5 have the greatest relevance for human alcohol dependence among the genes selected with odds ratios of 2.35 and 1.69, respectively. Replication analysis in study 2 confirmed an association of alcohol dependence with NR2A (odds ratio, 2.01) but showed no association with MGLUR5. Combined analysis of study 1 and study 2 exhibited a more significant association on the Cochran-Mantel-Haenszel test (P < .001) for NR2A; NR2A was associated with positive family history, early onset of alcoholism, and maximum number of drinks in adults as well as risky drinking patterns in adolescents. CONCLUSION: Genetic variations in NR2A have the greatest relevance for human alcohol dependence among the glutamatergic genes selected for their known alteration of alcohol effects in animal models.
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