Alcohol dependence and polymorphisms of serotonin-related genes

Genetic factors have a non-specific but significant impact on the risk of alcohol-dependence. Molecular genetic analyses are now less devoted to the genes involved in the metabolism of ethanol, focusing on core concepts of addiction, such as arousal, pleasure, reward, craving, and impulsivity. Indeed, the neuro-cognitive functions, temperament traits and psycho-behavioral specificities of patients with alcohol abuse or dependence led to select new sets of candidate genes. One of them are related to serotonin transmission, as serotonin modulates dopaminergic pathways, and is also stimulated by many addictive susbstances. The genetic analyses of serotonin in alcohol-dependence ore mainly focused on the serotonin transporter gene (5-HTT), as one polymorphism within the promoter has a functional impact. From the 16 case-control association studies yet performed, many are positive, and one family-based study showed a large excess of transmission of the short allele. We performed a meta-analysis of the case-control studies showing that the S allele could be a risk factor for a phenotype related to alcohol-dependence (OR=1.31), with still unknown boundaries. Other genes coding for serotonin receptors were analysed with mainly negative results, for example the 5-HT2A, 5-HT2C, 5-HT5A and 5-HT7 receptors. The 5-HTI1B could be more interesting as being located in a locus linked to alcohol preference in rodents, and associated with antisocial alcoholism in two human studies. Genetics may thus provide new insights about the different mechanisms which explain why some subjects are more at risk for the development of alcohol abuse or dependence. Genes involved in the transmission, reuptake and metabolism of serotonin constitute a set of candidate genes that could be involved in core aspects of alcoholism, such as the tendency to prefer immediate reward, despite negative consequences.