Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior.
BACKGROUND
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.


METHODS
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.


METHODS
Four university medical centers in the south of Germany.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Schumann
Gunter
G
Interdisciplinary Research Group Addiction, MRC-SGDP Center, Institute of Psychiatry at King's College, POB 080, London SE5 8AF, England. g.schumann@iop.kcl.ac.uk
Johann
Monika
M
Frank
Josef
J
Preuss
Ulrich
U
Dahmen
Norbert
N
Laucht
Manfred
M
Rietschel
Marcella
M
Rujescu
Dan
D
Lourdusamy
Anbarasu
A
Clarke
Toni-Kim
TK
Krause
Kristina
K
Dyer
Anne
A
Depner
Martin
M
Wellek
Stefan
S
Treutlein
Jens
J
Szegedi
Armin
A
Giegling
Ina
I
Cichon
Sven
S
Blomeyer
Dorothea
D
Heinz
Andreas
A
Heath
Simon
S
Lathrop
Mark
M
Wodarz
Norbert
N
Soyka
Michael
M
Spanagel
Rainer
R
Mann
Karl
K
D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000453:epidemiology / Q000235:genetics*; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002391:Catchment Area, Health; D004247:DNA / Q000032:analysis; D039721:Diagnostic and Statistical Manual of Mental Disorders; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D005819:Genetic Markers; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017470:Receptors, Glutamate / Q000235:genetics*; D012309:Risk-Taking; D016324:Sequence Tagged Sites; D009435:Synaptic Transmission / Q000502:physiology*
D027341:Excitatory Amino Acid Transporter 1; D005819:Genetic Markers; D017470:Receptors, Glutamate; C493394:SLC1A3 protein, human; D004247:DNA