Aims: Different vulnerability genes have been proposed in alcohol dependence, but replications are sparse, probably due to 1) phenotypical heterogeneity and 2) difficulties to rely on reliable definition of the correct phenotype. Indeed, specific subgroups of patients may be more directly concerned with some vulnerability genes, the actions of these genes being more directly related to their function. We postulated that three potential vulnerability genes, that were at least twice associated

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... h alcohol dependence, influence the extreme of the severity of alcohol dependence, i.e. mortality, through traits with which they were previously associated, namely impulsivity and antisocial personality disorder and the 5-HT1B gene, suicide attempt and the short allele of 5-HTTLPR, and addictive disorder co-morbidity and the DRD2 gene. Methods: We analysed the survival status of a male alcohol-dependent sample (n = 126) recruited 9 years before, and could compare 61 surviving patients to 41 patients who died during this period (representing 81.0% of the initial sample). Results: The main clinical characteristic that was associated with an increased mortality rate was a larger cumulative tobacco use (pack-years). We also found that the C allele of the 5-HT1b was the only one in excess in the non-surviving patients. Contrary to our hypothesis, impulsivity and antisocial personality disorder were not explaining the role of this gene. Conclusions: Even if there is a significant involvement of the 5-HT1B C allele, no intermediate phenotype was detected in our sample. The relatively short delay of 9 years and the somewhat old age at baseline of our patients could have limited the influence of psychiatric comorbidity or the specificities of alcohol dependence, explaining why the only detected co-factor was tobacco consumption. Tobacco dependence is therefore the main factor to explain mortality within the first decade, and the effect of this co-morbid condi-tion is not explained by three vulnerability genes previously associated to alcohol dependence.