Association between 5-HTTLPR genotypes and persisting patterns of anxiety and alcohol use : results from a 10-year longitudinal study of adolescent mental health

The serotonin transporter gene (5-HTT) encodes a transmembrane protein that plays an important role in regulating serotonergic neurotransmission and related aspects of mood and behaviour. The short allele of a 44 bp insertion/deletion polymorphism (S-allele) within the promoter region of the 5-HTT gene (5-HTTLPR) confers lower transcriptional activity relative to the long allele (L-allele) and may act to modify the risk of serotonin-mediated outcomes such as anxiety and substance use behaviours. The purpose of this study was to determine whether (or not) 5-HTTLPR genotypes moderate known associations between attachment style and adolescent anxiety and alcohol use outcomes. Participants were drawn from an eight-wave study of the mental and behavioural health of a cohort of young Australians followed from 14 to 24 years of age (Victorian Adolescent Health Cohort Study, 1992 - present). No association was observed within low-risk attachment settings. However, within risk settings for heightened anxiety (ie, insecurely attached young people), the odds of persisting ruminative anxiety (worry) decreased with each additional copy of the S-allele (B30% per allele: OR 0.77, 95% CI 0.62–0.97, P¼0.029). Within risk settings for binge drinking (ie, securely attached young people), the odds of reporting persisting high-dose alcohol consumption (bingeing) decreased with each additional copy of the S-allele (B35% per allele: OR 0.74, 95% CI 0.64–0.86, Po0.001). Our data suggest that the S-allele is likely to be important in psychosocial development, particularly in those settings that increase risk of anxiety and alcohol use problems.

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression

Background: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.

Methods/Design: To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.

Study eligibility criteria: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.

Data sources: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.  The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.

Discussion: Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Escitalopram efficacy in depression a cross-ethnicity examination of the serotonin transporter promoter polymorphism

Current evidence suggests that polymorphism in the serotonin transporter gene (5-HTTLPR) predicts antidepressant efficacy in whites but less so in Asians. However, it is not clear whether this effect can be observed for specific types of antidepressant drugs. White (n = 47) and Korean (n = 118) participants with major depressive disorder were treated with escitalopram and assessed over 8 weeks. Among those with the l/l but not l/s or s/s genotypes, whites had greater depression score reductions, response rates, and remission rates compared with Koreans. Our results suggest that 5-HTTLPR predicts escitalopram efficacy in an ethnicity-dependent manner.

Association between serotonin transporter genotype, brain structure and adolescent onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13–19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.

Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: a prospective imaging gene × environment analysis

A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of parental aggression or lower levels of positive parenting. The previously reported finding of S-allele carriers' increased risk of depression in adverse environments may, therefore, be partly because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume.