The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

There is inconsistent evidence of interaction between childhood adversities and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. It is hypothesized that genetic sensitivity to stress could be more specific to recurrent major depressive disorder (MDD). The aim of the study is to replicate a recent study which provided preliminary evidence of interaction between severity of childhood maltreatment and the 5-HTTLPR polymorphism in recurrent MDD. Participants included a well-characterized clinical sample of 70 recurrent MDD cases and 67 never psychiatrically ill controls, aged 18 years or over. Socio-demographic and clinical information form, Composite International Diagnostic Interview (CIDI), Childhood Trauma Questionnaire (CTQ), Beck Depression Inventory (BDI) were applied to both groups, along with genotyping. There was no interaction between childhood maltreatment and the 5-HTTLPR in relation to recurrent MDD. All forms of childhood maltreatment were reported as more severe by cases than controls, and there was an independent association between maltreatment and recurrent MDD. The path forward to detect genetic risk loci for depression remains challenging. Taking childhood maltreatment history into account could lead to a richer understanding of differences in biological correlates, genetic underpinnings, and outcomes.

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

Relationships between the serotonin transporter promoter polymorphism (5-HTTLPR), platelet serotonin transporter (SERT) binding and clinical phenotype were examined in 32 suicidal and 28 non-suicidal Ashkenazi Israeli adolescent psychiatric inpatients. The 5-HTTLPR polymorphism was not associated with transporter binding or with suicidality or other clinical phenotypes. However, in the suicidal group, a significant positive correlation between platelet SERT density and anger scores (n=32, r=.40; p=.027) and a negative correlation between platelet count and trait anxiety (n=32, r=-.42; p=.034) were observed.

Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder

Serotonin transporter gene and adverse life events in adult ADHD

HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism – 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

BackgroundThe aim of this study is to assess the association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder (PD).MethodsThis is a systematic review and meta-analysis of case-control studies with unrelated individuals of any ethnic origin examining the role of the 5-HTTLPR in PD according to standard diagnostic criteria (DSM or ICD). Articles published in any language between January 1996 and April 2007 were eligible. The electronic databases searched included PubMed, PsychInfo, Lilacs and ISI. Two separate analyses were performed: an analysis by alleles and a stratified analysis separating studies by the quality of control groups. Asymptotic DerSimonian and Laird's Q test were used to assess heterogeneity. Results of individual studies were combined using the fixed effect model with respective 95% confidence intervals.ResultsNineteen potential articles were identified, and 10 studies were included in this meta-analysis. No statistically significant association between 5-HTTLPR and PD was found, OR = 0.91 (CI95% 0.80 to 1.03, p = 0.14). Three sub-analyses divided by ethnicity, control group quality and Agoraphobia comorbidity also failed to find any significant association. No evidence of heterogeneity was found between studies in the analyses.ConclusionResults from this systematic review do not provide evidence to support an association between 5-HTTLPR and PD. However, more studies are needed in different ethnic populations in order to evaluate a possible minor effect.

Childhood attention deficit hyperactivity disorder (ADHD) symptomatology persists in a substantial proportion of cases into adult life. ADHD is highly heritable but the etiology of ADHD is complex and heterogeneous, involving both genetic and non-genetic factors. In the present article we analyzed the influence of both genetics and adverse life events on severity of ADHD symptoms in 110 adult ADHD patients. Subjects were genotyped for the norepinephrine transporter (NET), the catechol-O-methyltransferase (COMT), the serotonin transporter promoter polymorphism (SERTPR) and the more rare A/G variant within SERTPR. Three main outcomes were obtained: (1) adverse events showed a small but positive correlation with current ADHD severity; (2) NET, COMT and the A/G variant within SERTPR were not associated with ADHD severity; (3) taking into account stressors, the long (L) SERTPR variant showed a mild effect on ADHD, being associated with an increased severity, particularly as regard affective dysregulations; on the other hand, in subjects exposed to early stressors, it showed a protective effect, as compared to the short (S) variant. In conclusion, our data support the role of environmental factors in adult ADHD symptomatology. SERTPR may be involved in some features of the illness and act as a moderator of environmental influences in ADHD.

Stressful life events and the serotonin transporter gene ( 5-HTT ) in recurrent clinical depression

Anxiety-related personality traits, such as NEO neuroticism and TCI/TPQ harm avoidance, have been shown to have significant genetic components. To date, however, no specific genetic variants that contribute to these traits have been conclusively identified. At least 26 studies have investigated a putative association between a functional serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. The results of these studies have been inconsistent with some studies finding evidence for an association, and others not. We performed a meta-analysis of all applicable studies investigating this association. In the overall analysis (N = 5,629 subjects), we found suggestive evidence for an association between the 5-HTTLPR short allele (s) and increased anxiety-related personality trait scores (P = 0.087). However, we also found strong evidence for heterogeneity. This heterogeneity is largely explained by substantial variation between the studies in the inventory used. When the analysis was stratified by inventory type, there was a significant association between 5-HTTLPR and NEO neuroticism (P = 0.000016), a non-significant association between 5-HTTLPR and TCI/TPQ harm avoidance (P = 0.166), and no association between 5-HTTLPR and other anxiety-related personality traits (P = 0.944). There was no evidence that these results were either due to publication bias or accounted for by any one single study. We conclude that there is a strong association between the serotonin transporter promoter variant and neuroticism as measured in the NEO personality inventory and that non-replications are largely due to small sample size and the use of different inventories.

BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: A prospective study

Association between a serotonin transporter promoter polymorphism (5HTTLPR) and personality disorder traits in a community sample

Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder

Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

The serotonin transporter promoter polymorphism (5-HTTLPR) is associated with type 2 diabetes