ReviewThe serotonin transporter gene and risk for alcohol dependence: A meta-analytic review
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.
Section snippets
Search strategy
The identification of articles began with selecting the published studies analyzed by Feinn et al. (2005). To capture studies published since that time, the search engines PubMed, PsychInfo, and the Cochrane library were examined through March 2009 using the following search terms in combination: serotonin transporter gene, 5HTTLPR, SCL6A4, alcohol dependence, alcohol use disorders, and alcoholism. Finally, the reference section of each of the relevant publications identified through these
Trial flow
Fig. 1 details the study selection process. Our search methods yielded a total of 145 potential studies. Of these, 22 met our inclusion criteria (15 were included in the Feinn et al., 2005 paper). Two studies included in the Feinn and colleagues meta-analysis (Edenberg et al., 1998, Lichtermann et al., 2000) were not included in the analysis because they used the transmission disequilibrium test (TDT) methodology, which may compromise the ease of comparison to the majority of studies using
Discussion
This study evaluated the magnitude of the association between allelic variation at 5HTTLPR and alcohol dependence in 22 case–control studies. Findings indicated a significant but modest association, characterized by a 15% greater likelihood of the presence of at least 1 s allele among individuals with alcohol dependence relative to control participants. This finding provides an estimate of the strength of results from a prior meta-analysis (Feinn et al., 2005) and extends these results to
Conflict of interest
Dr. Hofmann is a paid consultant by Schering-Plough. Dr. Otto has served as a consultant and receives research support from Organon (Schering-Plough). All other authors have no conflicts to report.
Role of funding source
Effort on this article was supported in part by NIMH grant MH078308 to Dr. Hofmann and NIDA award DA017904 to Dr. Otto. The NIMH and NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
All authors were involved in study design and decisions relative to the methodology. Ms. McHugh, Ms. Asnaani, and Ms. Sawyer managed the literature searches and data extraction. Ms. Asnaani and Ms. Sawyer undertook the statistical analysis, and all authors contributed to data interpretation. Ms. McHugh primarily wrote the first draft of the manuscript, with all authors writing sections of this draft. All authors contributed to and have approved the final manuscript.
Acknowledgements
We thank Dr. Winfried Rief for his input during the early stage of this study.
References (58)
- et al.
Genetic polymorphisms of alcohol and aldehyde dehydrogenase, dopamine and serotonin transporters in familial and non-familial alcoholism
Eur. Neuropsychopharmacol.
(2006) - et al.
Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia
Neurosci. Lett.
(2004) - et al.
Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior
Biol. Psychiatry
(2000) - et al.
HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression
Biol. Psychiatry
(2008) - et al.
Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence?
Alcohol
(1999) - et al.
Early-emerging cognitive vulnerability to depression and the serotonin transporter promoter region polymorphism
J. Affect Disord.
(2008) - et al.
Polymorphisms of the dopamine D2 receptor, serotonin transporter, and GABAA receptor b3 subunit genes and alcoholism in Mexican-Americans
Alcohol
(2004) - et al.
Association of the serotonin transporter gene polymorphism with Korean male alcoholics
J. Psychiatr. Res.
(2005) Alcohol dependence and gene x environment interaction in emotion regulation: is serotonin the link?
Eur. J. Pharmacol.
(2005)- et al.
Association between suicide attempts and 5-HTTLPR-S-allele in alcohol-dependent and control subjects: further evidence from a German alcohol-dependent inpatient sample
Biol. Psychiatry
(2001)
Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence
Neurosci. Lett.
Serotonin transporter gene variants in alcohol dependent subjects with dissocial personality disorder
Biol. Psychiatry
Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study
Biol. Psychiatry
Serotonin transporter gene polymorphisms in alcohol dependence
Alcohol
Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database
Nat. Genet.
Diagnostic and Statistical Manual of Mental Disorders
Diagnostic and statistical manual of mental disorders
Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients
J. Abnormal Psych.
Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence
Alcohol Alcohol
Comprehensive Meta-analysis, version 2
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
MAOA-uVNTR polymorphism in a Brazilian sample: further support for the association with impulsive behaviors and alcohol dependence
Am. J. Med. Genet. B: Neuropsychiatr. Genet.
5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression
Neuropsychopharmacology
Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample
Psychiatr. Genet.
A family-based analysis of whether the functional promoter alleles of the serotonin transporter gene HTT affect the risk for alcohol dependence
Alcohol Clin. Exp. Res.
Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence
Am. J. Med. Genet. B: Neuropsychiatr. Genet.
Association studies of neurotransmitter gene polymorphisms in alcoholic Caucasians
Ann. N Y Acad. Sci.
Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects
Hum. Genet.
Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism: Influence of the serotonin transporter gene on comorbid disorders among alcohol-dependent individuals
Arch. Womens Ment. Health
Cited by (88)
A review of the genetic basis of problematic Internet use
2022, Current Opinion in Behavioral SciencesAlcohol use disorders among adult children of alcoholics (ACOAs): Gene-environment resilience factors
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryGenetics of alcohol use disorder
2019, Personalized Psychiatry