Feinn R, Nellissery M, Kranzler HR. Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 133: 79-84

Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut 06030-2103, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 02/2005; 133B(1):79-84. DOI: 10.1002/ajmg.b.30132
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The neurotransmitter serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5-HT transporter protein (5-HTT) regulates 5-HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion-deletion polymorphism in the 5-HTT-linked promoter region (5-HTTLPR) have yielded inconsistent results. We conducted a meta-analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5-HTTLPR alleles and AD. The frequency of the short (S) allele at 5-HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03-1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co-morbid psychiatric condition or an early-onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11-1.63)]. Allelic variation at 5-HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co-occurring clinical feature.

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    • "As a result, additional pharmacogenetic studies that carefully phenotype participants are needed to guide clinical care. Because many studies have found the S allele to be associated with AD concurrent with an Axis I disorder (Thompson et al., 2000; Feinn et al., 2005; McHugh et al., 2010; Herman and Balogh, 2012), it seems paradoxical that treatment response to SSRIs may be greater in patients with one or two L alleles. This phenomenon may result from the increased expression of 5-HTT associated with the L allele and present opportunities for the development of SSRI drugs with improved transporter binding. "
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    ABSTRACT: SLC6A4, the gene encoding the serotonin transporter protein (5-HTT), has been extensively examined as a risk factor for alcohol dependence (AD). More recently, variability in the transporter gene was identified to be a potential moderator of treatment response to serotonergic medications such as ondansetron and sertraline. There is an insertion-deletion polymorphism in the promoter region (5-HTTLPR) of the SLC6A4, with the most common alleles being a 14-repeat short (S) allele and a 16-repeat long (L) allele. The S allele has often been associated with AD. By contrast, the L allele has been associated with pharmacological responsiveness in some individuals with AD. Differences in clinical phenotype may determine the utility of the 5-HTTLPR polymorphism as a moderator of pharmacological interventions for AD. We review the AD typology and disease onset in the context of pharmacogenetic and genomic studies that examine the utility of 5-HTTLPR in improving treatment outcomes. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
    Alcohol and Alcoholism 08/2015; DOI:10.1093/alcalc/agv090 · 2.89 Impact Factor
    • "Recently published review of candidate gene-based studies, linkage studies and genome-wide association studies pointed out a limited role of individual genetic variants in the risk for alcohol dependence, although single risk variants within neurotransmitter signalling pathways may help to deepen the understanding of the underlying pathophysiology of alcohol dependence [21]. Serotonin (5-HT) has been shown to regulate alcohol consumption in both animals and humans and is considered to be involved in many aspects of alcohol consumption, abuse and dependence [10]. Studies investigating alcohol use disorders have recently focused on the neuronal tryptophan hydroxylase 2 (TPH2) gene [24]. "
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    ABSTRACT: Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p = 0.038) and GTAA and GGGT were more common (p = 0.011 and p = 0.021 respectively) in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p = 0.045 and p = 0.001, respectively), rs4290270 with depressive and anxiety traits (p = 0.040 and p = 0.025, respectively) and rs4570625 with aggressive traits (p = 0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p = 0.003). Only association between rs1843809 and the BDHI score (p = 0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p = 0.001 and p < 0.001, respectively) in currently dependent patients remained significant after applying the Bonferroni's correction. Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 07/2015; 604. DOI:10.1016/j.neulet.2015.07.037 · 2.03 Impact Factor
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    • "However the association with specific alleles remained inconsistent, with variations according to alcohol subtype, type of drinking behavior, ethnicity, comorbid diagnoses or age of onset. Findings of meta-analyses that have examined the role of the 5-HTTLPR in AD indicated that there was a significant but modest association with the S allele (Feinn et al., 2005; McHugh et al., 2010; Cao et al., 2013). "
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    ABSTRACT: The role of the serotonin transporter gene (SLC6A4) in alcohol dependence (AD) is still unclear. In this paper, we have evaluated the association of the SLC6A4 gene polymorphisms 5-HTTLPR and rs25531 in AD and assessed the polymorphic patterns both in alcoholics and in healthy people of an Italian population. Genotyping of the 5-HTTLPR (L/S) and rs25531 (A/G) polymorphisms of the SLC6A4 gene was performed on 403 alcoholics outpatients and 427 blood donors. Comparing AD and control populations and taking into account statistical correction for multiple testing, we found no statistically significant differences for 5-HTTLPR (L/S) and rs25531 polymorphisms in terms of either genotypes or alleles frequencies. By univariate ANOVA, a statistically significant difference was found in the onset of AD: the mean age of onset resulted to be of 25.4 years in males in respect to 28.1 in females. In particular in males, the early AD onset was different, in a statistically significant manner, depending on the presence of at least one S or Lg allele (24.6 years) in respect to La homozygotes (27.5 years) (P = 0.03). These findings suggest that genetic factors contribute, together with gender and age, to the onset differences in alcohol-dependent phenotypes. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
    Alcohol and alcoholism (Oxford, Oxfordshire). Supplement 03/2015; 50(3). DOI:10.1093/alcalc/agv014
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