Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior

Abstract

Background: Dysfunction of serotoninergic transmission could predispose to excessive alcohol consumption and dependence. The functional polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with different disorders, including alcoholism. Considering the likelihood of heterogeneity in the “alcohol dependence” phenotype, 5-HTTLPR may be more specifically implicated in subsamples of patients or in related traits of alcoholism, such as impulsivity.

Methods: We analyzed the role of this functional polymorphism in the risk for suicide attempt in a population of male alcohol-dependent subjects. One hundred ten male alcohol-dependent patients (DSM-III-R criteria), French for at least two generations, were personally interviewed with the Diagnostic Interview for Genetic Studies and compared with 61 unaffected blood donors.

Results: The “short” (S) allele of the 5-HTTLPR appeared to be unrelated to alcohol dependence and comorbid depression in our sample, but was found associated with an increased risk for suicide attempts. This association was predominantly observed in severe and repetitive suicide attempts, with a significant dose effect of the S allele (0, 1, or 2) on the number and the severity of suicide attempts.

Conclusions: Mood disorders and alcohol dependence may interact with a genetic (relative) deficiency in serotonin reuptake, thereby increasing the risk for aggressive/impulsive behaviors such as suicide attempts.

Introduction

Evidence has accumulated for the last years that serotonergic neurotransmission is involved in alcoholism McBride et al 1993, Sellers et al 1992. Thus alcohol-drinking behavior seems to be associated with low activity levels of central serotonin (5-HT) systems Ferreira and Soares-Da-Silva 1991, LeMarquand et al 1994b, Zhou et al 1994. Alterations in 5-HT uptake have also been described in alcohol-dependent patients Ernouf et al 1993, Heinz et al 1998 that may sustain such alcohol–5-HT relationships because selective 5-HT reuptake inhibitors, such as fluoxetine, sertraline, and citalopram, regularly produce a decrease in alcohol craving and drinking in alcoholic patients Balldin et al 1994a, Balldin et al 1994b, Higley et al 1998, Lejoyeux 1996, Lu et al 1994, Naranjo et al 1994.

Alcoholic subjects are dramatically exposed to suicidal behavior (Kessler et al 1994) and suicide mortality (Rossow and Amundsen 1995), which may also be causally related to altered 5-HT neurotransmission. Indeed, low levels of 5-HT and/or its metabolite 5-hydroxyindoleacetic acid (5-HIAA) have regularly been found in blood and cerebrospinal fluid (CSF) of subjects who attempted suicide (Pihl and LeMarquand 1998). Interestingly, alterations in 5-HT uptake have also been reported in these subjects Ellis and Salmond 1994, Meltzer et al 1981. The interaction between alcoholism and 5-HT uptake may thus be relevantly tested to explain the increased risk for suicidal behavior in alcohol-dependent patients.

Polymorphism of the gene encoding the 5-HT transporter (5-HTT) notably concerns its promoter (Heils et al 1996). The region between base pair (bp) 1376 and bp 1027 contains 16 tandem repeats of a 20- to 23-bp G+C rich sequence. Two common forms of this region were found in a white population: a 528-bp allele with 16 repeats (“long” [L] allele) and a 448-bp allele (“short” [S] allele) with a deletion of 44 bp extending from bp 1255 to bp 1212. The 528-bp long allele of the 5-HTT promoter is two- to threefold more active in driving transcription than the 484-bp allele in transfection experiments (Heils et al 1996). In addition, 5-HT uptake is twice as high in lymphoblastoid cells from individuals homozygous for the 528-bp allele as in cells from individuals of the other genotypes (Lesch et al 1996). The potential role that this functional polymorphism in the 5-HTT promoter may play in personality traits and psychiatric diseases has already been the matter of numerous studies; however, to date, rather controversial data have been reported regarding a possible association of either the short or the long allele with sometimes mood disorders and sometimes anxiety-related disorders Ball et al 1997, Bellivier et al 1997, Collier et al 1996, Ewald et al 1998, Gutierrez et al 1998, Jorm et al 1998, Kunugi et al 1997, Lesch et al 1996, Matsushita et al 1997, McDougle et al 1998, Nakamura et al 1997, Rees et al 1997.

Similarly, conflicting data have been reported about the possible association of polymorphism of the 5-HTT gene promoter with alcoholism. Thus, Sander et al (1998) and Schmidt et al (1997) found that the frequency of the short allele is significantly increased in alcoholic patients with severe dependence as compared with nonalcoholic control subjects. On the other hand, Türker et al (1998) noted the existence of a significant association between the short allele of the 5-HTT gene promoter and high ethanol tolerance in young adults. In contrast, Edenberg et al (1998) and Jorm et al (1998) could not find any association between polymorphism of the 5-HTT gene promoter and alcohol misuse and dependence.

Because heterogeneity in the population of alcoholic patients might have contributed to these discrepancies, further investigations on a possible association between this polymorphism and various subgroups of alcoholics have been performed. Distinction of subgroups based on the presence and type of suicidal behavior allowed the discovery of a significant association between the presence of the short allele of the 5-HTT gene promoter and severe suicide attempts in alcoholic-dependent patients.