Multi-Cultural Association of the Serotonin Transporter Gene (SLC6A4) with Substance Use Disorder

Abstract

A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR) ¼ 0.54 (0.35, 0.84); 0.0024 with OR ¼ 0.77 (0.66, 0.91); 0.018 with OR ¼ 1.38 (1.06, 1.81); and 0.028 with OR ¼ 0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR ¼ 0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR ¼ 1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.

Maladaptive Decision Making and Substance Use Outcomes in High-Risk Individuals: Preliminary Evidence for the Role of 5-HTTLPR Variation

“…Analyses were based on the recessive model that presumes that SS individuals differ from those with 0 or 1 copy of the S allele. This model appears to be most highly associated with increased odds of developing an SUD (Cao et al, 2013).…”

“…Variation in 5-HTTLPR has also been associated with AD, such that short-allele carriers have increased odds of being diagnosed with AD and other SUDs, although some results are equivocal (Cao et al, 2013;Feinn et al, 2005). Thus, heritable variation in 5-HTTLPR may contribute to decision-making defi cits in HR offspring.…”

A meta-analysis of the associations between the SLC6A4 promoter polymorphism (5HTTLPR) and the risk for alcohol dependence

“…A recent meta-analysis by Cao et al (2013) where case-control and family-based studies were evaluated for the association between SLC6A4 promoter polymorphism (5HTTLPR) and alcohol, heroin, cocaine and methamphetamine abuse found a significant association with alcohol dependence (Cao, 2013). Our meta-analysis excluded family-based studies that used PDT, TDT and haplotype relative risk methodologies, which may have been a contributing factor for the null finding.…”

Alcohol Dependence and Genetic Variability in the Serotonin Pathway among Currently and Formerly Alcohol-Dependent Males

“…However, studies have reported conflicting results [38,39,40,41,42,43]. Meta-analyses have shown a modest but significant association of the S allele with the risk of alcohol dependence, with the greatest effect observed among individuals with a comorbid psychiatric condition or early onset or more severe alcohol dependence [5,44,45,46]. The risk allele 5-HTTLPR S was significantly more frequent in Asians (73%) than in Europeans (43%) and Mexicans (53%), whereas the 5- HTTLPR L allele was the risk allele in African populations [46].…”

“…Meta-analyses have shown a modest but significant association of the S allele with the risk of alcohol dependence, with the greatest effect observed among individuals with a comorbid psychiatric condition or early onset or more severe alcohol dependence [5,44,45,46]. The risk allele 5-HTTLPR S was significantly more frequent in Asians (73%) than in Europeans (43%) and Mexicans (53%), whereas the 5- HTTLPR L allele was the risk allele in African populations [46]. One study in a Han Chinese population reported that alcohol-dependent patients were more likely to carry the low-functional genotypes of 5-HTTLPR, such as SS, SL G , or L G L G [47], while other studies which considered triallelic functional 5-HTTLPR found no such association between the selected SNP and alcohol dependence [48].…”