Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence.
The present study tested the hypothesis that the short, low activity variant of a biallelic polymorphism in the 5' regulatory region of the human serotonin transporter (5-HTT) gene confers susceptibility to severe alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our population-based association analysis included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol-dependent subjects by a history of alcohol withdrawal seizure or delirium. The frequency of the short allele (S) was significantly increased in the severely affected alcoholics, compared with that in the controls (X2 = 3.87, df = 1, nominal p = 0.049). The post-hoc exploration indicated that this allelic association resulted exclusively from a significant excess of the S/S genotype in the severely affected alcoholics (p = 0.035), suggesting a recessively acting effect. Consistently, we found a weak but significant correlation (p = 0.013) between the frequency of the S/S genotype and severity of withdrawal symptoms (WDS): no WDS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR = 1.44), and severe WDS with either withdrawal seizure only or delirium only (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30). Further studies are required to test whether the tentative genotype-phenotype relationship occurred by chance or reflects a real genotypic association between a recessively modifying effect of the short variant of the functional 5-HTT promoter polymorphism and alcohol withdrawal vulnerability.
Sander
T
T
Department of Psychiatry, University Hospital Benjamin Franklin, Free University of Berlin, Germany.
Harms
H
H
Lesch
K P
KP
Dufeu
P
P
Kuhn
S
S
Hoehe
M
M
Rommelspacher
H
H
Schmidt
L G
LG
D000328:Adult; D000430:Alcohol Withdrawal Delirium / Q000235:genetics; D000437:Alcoholism / Q000235:genetics* / Q000534:rehabilitation; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins