Association Analysis of a Regulatory Variation of the Serotonin Transporter Gene with Severe Alcohol Dependence

• Published in: Alcoholism, clinical and experimental research Vol. 21; no. 8; pp. 1356 - 1359
• Main Authors: Sander, Thomas, Harms, Helmut, Lesch, Klaus-Peter, Dufeu, Peter, Kuhn, Silke, Hoehe, Margret, Rommelspacher, Hans, Schmidt, Lutz G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.1997; Lippincott Williams & Wilkins
• Subjects: Adult; Alcohol Dependence; Alcohol Withdrawal Delirium - genetics; Alcoholism - genetics; Alcoholism - rehabilitation; Alcoholism and acute alcohol poisoning; Alleles; Association; Biological and medical sciences; Carrier Proteins - genetics; Female; Genes, Recessive - genetics; Genes, Regulator - genetics; Genetic Variation; Genetics; Genotype; Humans; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Serotonin Plasma Membrane Transport Proteins; Serotonin Transporter; Toxicology; Withdrawal Syndrome; Human; Correlation; Ethanol; Serotonin; Toxicity; Alcoholism; Genotype; Allele; Phenotype; Toxicogenetics; Dependence; Predisposition; Genetics; Carrier protein; Polymorphism
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/j.1530-0277.1997.tb04462.x

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 WOS [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.