The serotonin transporter gene and risk for alcohol dependence: A meta-analytic review

Abstract

Previous studies have implicated a relationship between particular allelic variations of the serotonin transporter gene (5HTTLPR) and alcohol dependence. To provide a current estimate of the strength of this association, particularly in light of inconsistent results for 5HTTLPR, we conducted a meta-analytic review of the association between 5HTTLPR and a clinical diagnosis of alcohol dependence. Of 145 studies initially identified, 22 (including 8050 participants) met inclusion criteria. Results indicated that there was a significant albeit modest association between alcohol dependence diagnosis and the presence of at least 1 short allele (OR = 1.15, 95% CI = 1.01, 1.30, p < .05). Slightly more robust results were observed for participants who were homogeneous for the short allele (OR = 1.21, 95% CI = 1.02, 1.44, p < .05). These results were unrelated to sex and race/ethnicity of participants; however, the effect size was moderated by study sample size and publication year. Additionally, the fail-safe N analysis indicated potential publication bias. Therefore, although our review indicates that there is a significant association between 5HTTLPR and alcohol dependence diagnosis, this result should be interpreted with caution.

Introduction

Despite the large body of research dedicated in recent years to identifying genetic risk factors for psychiatric disorders, results have been characterized by modest effect sizes and limited replication (e.g., Allen et al., 2008, Risch et al., 2009). For example, in a meta-analytic review of 14 studies capturing over 14,000 participants, Risch et al. (2009) failed to confirm the landmark Caspi et al. (2003) study identifying an interaction between the serotonin transporter gene (5HTTLPR) and life stress on the risk for depression. Instead, Risch et al. (2009) noted a replication failure among studies subsequent to Caspi et al. (2003); across studies, Risch et al. (2009) found no consistent evidence for either a direct relationship between 5HTTLPR and depression, or an interaction between the gene and life events on the risk for depression. This recent finding underscores the importance of quantitative analyses to evaluate the magnitude of effect sizes across studies. In the present study, we conducted an effect size analysis of the association between the serotonin transporter gene and alcohol dependence.

In the search for potential genetic risk factors for substance dependence, much work has focused on genes involved in neurotransmitter regulation. For example, associations with alcohol dependence have been established for the dopamine transporter gene (Kohnke et al., 2005), the D2 dopamine receptor gene (Smith et al., 2008), and the monoamine oxidase A gene (Contini et al., 2006). Given the relevance of serotonin to alcohol use and abuse (see Tabakoff and Hoffman, 2004), the serotonin transporter gene has also received substantial research attention.

A common polymorphism at the promoter region of serotonin transporter gene influences the reuptake of serotonin, thereby regulating its concentration in the synaptic cleft. Among individuals with one or more copies of the short allele at this location, serotonin reuptake is attenuated, resulting in increased availability of serotonin in the synapse and downregulation of post-synaptic binding sites (see Lesch et al., 1996). Allelic variation at 5HTTLPR has been implicated in alcohol use disorders relative to several domains, such as alcohol craving (Bleich et al., 2007) and relapse (Pinto et al., 2008); however, results have been mixed, with studies also failing to find an association between such variables and 5HTTLPR (e.g., Kohnke et al., 2006, Rasmussen et al., 2009). A more consistent finding in the literature has been the link between 5HTTLPR and alcohol dependence diagnosis. A meta-analytic review of 17 studies (including 3489 alcohol dependent and 2325 control participants) found support for a significant association between this polymorphism and diagnosis, with alcohol dependent participants being 18% more likely to possess at least 1 short (s) allele relative to control participants (Feinn et al., 2005). Given these initial promising results for an association between 5HTTLPR and alcohol dependence, the number of studies in this area has almost doubled since the publication of the Feinn et al. (2005) review. The goal of the current study was to attempt to replicate the findings of Feinn et al. (2005), by updating their review with the studies published subsequent to their analysis, and to systematically assess for publication bias.