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Systematic Analysis of Glutamatergic Neurotransmission Genes in Alcohol Dependence and Adolescent Risky Drinking Behavior
Gunter Schumann, MD;
Monika Johann, MD;
Josef Frank, MA;
Ulrich Preuss, MD;
Norbert Dahmen, MD;
Manfred Laucht, PhD;
Marcella Rietschel, MD;
Dan Rujescu, MD;
Anbarasu Lourdusamy, PhD;
Toni-Kim Clarke, MRes;
Kristina Krause, MA;
Anne Dyer, PhD;
Martin Depner, MA;
Stefan Wellek, PhD;
Jens Treutlein, PhD;
Armin Szegedi, MD;
Ina Giegling, PhD;
Sven Cichon, PhD;
Dorothea Blomeyer, MA;
Andreas Heinz, MD;
Simon Heath, PhD;
Mark Lathrop, PhD;
Norbert Wodarz, MD;
Michael Soyka, MD;
Rainer Spanagel, PhD;
Karl Mann, MD
Arch Gen Psychiatry. 2008;65(7):826-838.
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.
Author Affiliations: Central Institute of Mental Health, Mannheim, Germany (Drs Schumann, Laucht, Rietschel, Dyer, Wellek, Treutlein, Spanagel, and Mann, Mssrs Frank and Depner, and Ms Blomeyer); MRC, SGDP Center & Division of Psychological Medicine, Institute of Psychiatry at King's College, London, England (Drs Schumann and Lourdusamy and Mss Clarke and Krause); Department of Psychiatry and Psychotherapy, University of Regensburg Bezirksklinikum, Regensburg, Germany (Drs Johann and Wodarz); Department of Psychiatry and Psychotherapy, Martin-Luther-University, Halle, Germany (Dr Preuss); Department of Psychiatry and Psychotherapy, University of Mainz, Mainz, Germany (Dr Dahmen); Department of Psychology, University of Potsdam, Potsdam, Germany (Dr Laucht); Department of Psychiatry and Psychotherapy, University of Munich, Munich, Germany (Drs Rujescu, Giegling, and Soyka); Global Clinical Development, Organon, Roseland, New Jersey (Dr Szegedi); Department of Genomics, Life and Brain Centre, University of Bonn, Bonn, Germany (Dr Cichon); Department of Psychiatry and Psychotherapy; Charité-Universitätsmedizin, Berlin, Germany (Dr Heinz); and Centre National de Génotypage, Evry, France (Drs Heath and Lathrop).
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