Systematic analysis of Glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior

被引：92

作者：

Schumann, Gunter ^{[1
,2
,3
]}

Johann, Monika ^{[4
]}

Frank, Josef ^{[1
]}

Preuss, Ulrich ^{[5
]}

Dahmen, Norbert ^{[6
]}

Laucht, Manfred ^{[1
,7
]}

Rietschel, Marcella ^{[1
]}

Rujescu, Dan ^{[8
]}

Lourdusamy, Anbarasu ^{[3
]}

Clarke, Toni-Kim ^{[3
]}

Krause, Kristina ^{[3
]}

Dyer, Anne ^{[1
]}

Depner, Martin ^{[1
]}

Wellek, Stefan ^{[1
]}

Treutlein, Jens ^{[1
]}

Szegedi, Armin ^{[9
]}

Giegling, Ina ^{[8
]}

Cichon, Sven ^{[10
]}

Blomeyer, Dorothea ^{[1
]}

Heinz, Andreas ^{[11
]}

Heath, Simon ^{[12
]}

Lathrop, Mark ^{[12
]}

Wodarz, Norbert ^{[4
]}

Soyka, Michael ^{[8
]}

Spanagel, Rainer ^{[1
]}

Mann, Karl ^{[1
]}

机构：

[1] Cent Inst Mental Hlth, D-6800 Mannheim, Germany

[2] Kings Coll London, Inst Psychiat, Interdisciplinary Res Grp Addict, MRC,SGDP Ctr, London SE5 8AF, England

[3] Kings Coll London, Inst Psychiat, Div Psychol Med, London SE5 8AF, England

[4] Univ Regensburg, Dept Psychiat & Psychotherapy, Bezirksklinikum, Regensburg, Germany

[5] Univ Halle Wittenberg, Dept Psychiat & Psychotherapy, Halle, Germany

[6] Johannes Gutenberg Univ Mainz, Dept Psychiat & Psychotherapy, Mainz, Germany

[7] Univ Potsdam, Dept Psychol, Potsdam, Germany

[8] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany

[9] Organon, Global Clin Dev, Roseland, NJ USA

[10] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[11] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany

[12] Ctr Natl Genotypage, Evry, France

来源：

ARCHIVES OF GENERAL PSYCHIATRY | 2008年 / 65卷 / 07期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1001/archpsyc.65.7.826

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

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.

引用

页码：826 / 838

页数：13

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