Original ArticlesSerotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder
Introduction
Alcohol dependence is a multifactorial disorder caused by complex interaction of genetic and environmental factors (Merikangas 1990). Heritable influences account for approximately 40% of the total variance of alcohol dependence (Pickens et al 1991). Various typologies of alcohol dependence have been proposed that are based on differences in genetic disposition. Dissocial behavior and early onset of alcoholism consistently distinguished a subgroup of alcoholics (type-2) with substantial genetic predisposition (Cloninger 1987). Type-2 alcoholics exhibit impulsive-aggressive and risk-taking behavior that is frequently associated with dissocial personality disorder.
Deficits in central serotonergic neuroregulation have been consistently observed in alcoholics marked by an early onset and impulsive-aggressive behavior Cloninger 1987, Limson et al 1991, LeMarquand et al 1994a, LeMarquand et al 1994b, Fils-Aime et al 1996, Coccaro et al 1996, Higley et al 1996a, Higley et al 1996b, Hen 1996. According to Cloninger’s neurogenetic tripartite theory of personality, alcohol-dependent subjects with dissocial behavior exhibit a temperamental profile that is high in novelty seeking, low in harm avoidance, and low in reward dependence (Cloninger 1987). The personality dimension of harm avoidance is positively correlated with the activity of mesolimbic serotonergic neurons (Cloninger 1987). The important role of the serotonin transporter protein in terminating the synaptic actions of serotonin (5-HT) by sodium-dependent reuptake of 5-HT into the presynaptic terminals defines the human serotonin transporter gene (locus symbol: SLC6A4) as a high-ranking candidate gene for alcohol-seeking and risk-taking behavior LeMarquand et al 1994a, LeMarquand et al 1994b, Goldman 1996, Lesch et al 1996. Moreover, an autosomal recessive and female-restricted quantitative trait locus (Alcp2) controlling alcohol preference in C57BL/6J mice has been assigned to the chromosomal region in which the murine serotonin transporter gene is located (Melo et al 1996). Alcp2 accounts for 18% of the total variance in alcohol preference of the female population and shows evidence for a parent-of-origin effect.
A common biallelic polymorphism of a repetitive imperfect 20–23 bp element has been found in the 5′ regulatory region of the human SLC6A4 gene that differentially drives the transcription of a reporter gene in transfection studies Heils et al 1996, Lesch et al 1996. The 44 bp shorter allele (S) exhibits a reduced basal transcription (∼30%) compared to the larger allele (L), resulting in a decreased SLC6A4 expression and diminished 5-HT uptake in human lymphoblast cell lines (Lesch et al 1996). Recently, an allelic association of anxiety-related traits with the S allele of the regulatory SLC6A4 polymorphism has been reported (Lesch et al 1996). Therefore, the question arises whether this functional SLC6A4 polymorphism modulates central serotonergic transmission, and, thereby, contributes to individual differences in alcohol-seeking and risk-taking behavior, as observed in dissocial alcoholics. The present association study was designed to test the hypothesis that allelic variation of the regulatory SLC6A4 polymorphism confers susceptibility to alcohol-seeking and risk-taking behavior in dissocial alcoholics.
Section snippets
Subjects
The study protocol was approved by the Ethics Committee of the University Hospital Rudolf Virchow at the Free University of Berlin. Written informed consent was obtained from all participants before the start of the study. All subjects were unrelated individuals of German descent. The diagnostic assessment was performed without knowledge of the genotype data.
Controls
Two hundred and sixteen control subjects were recruited from two sources: 105 of the controls were randomly chosen from a panel of
Results
The frequency of the S allele in 432 chromosomes of German controls was 39.4% with an observed heterozygosity of 46.3%. The S allele frequencies among both control subsamples did not differ significantly (χ2 = 0.01, df = 1, p = 0.92; two-tailed). The genotype frequencies and the S allele frequencies in the controls, the entire sample of alcohol-dependent subjects, and the subgroup of dissocial alcoholics are shown in Table 1. A trend towards an increased frequency of the S allele was observed
Discussion
Taking into account the explorative approach employed in the present association study, none of the results reached statistical significance when a correction for multiple testing was implemented in the statistical analysis. However, without correction for multiple testing, the present data might indicate a modifying influence of the S allele of the 5′ regulatory SLC6A4 polymorphism to alcohol-seeking and dissocial behavior. This possible association resulted predominantly from a nonsignificant
Acknowledgements
Supported by the Deutsche Forschungsgemeinschaft (He 916/7-2) and the Kommission für Forschung und wissenschaftlichen Nachwuchs of the Free University of Berlin.
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