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 v ariant of a biallelic polymorphism in the 5' regulatory region of the human serotonin transporter (5-HTT) gene confers susceptibility to sev ere alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our population-based association analys is included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol-dependen t 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 (chi( 2) = 3.87, df = 1, nominal p = 0.049). The post-hoc exploration indica ted that this allelic association resulted exclusively from a signific ant excess of the S/S genotype in the severely affected alcoholics (p = 0.035), suggesting a recessively acting effect. Consistently, we fou nd a weak but significant correlation (p = 0.013) between the frequenc y of the S/S genotype and severity of withdrawal symptoms (WDS): no WD S [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 on ly (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8% , OR = 2.30). Further studies are required to test whether the tentati ve genotype-phenotype relationship occurred by chance or reflects a re al genotypic association between a recessively modifying effect of the short variant of the functional 5-HTT promoter polymorphism and alcoh ol withdrawal vulnerability.