TY  - JOUR
A1  - Juhasz, Gabriella
A1  - Gonda, Xenia
A1  - Hullam, Gabor
A1  - Eszlari, Nora
A1  - Kovacs, David
A1  - Lazary, Judit
A1  - Pap, Dorottya
A1  - Petschner, Peter
A1  - Elliott, Rebecca
A1  - Deakin, John Francis William
A1  - Muir Anderson, Ian
A1  - Antal, Peter
A1  - Lesch, Klaus-Peter
A1  - Bagdy, Gyorgy
T1  - Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors
JF  - PLoS ONE
N2  - Background 
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. 

Methods 
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. 

Results 
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (\(\leq\)30) individuals. 

Limitations 
Our study is cross-sectional and applies self-report questionnaires. 

Conclusions 
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
KW  - serotonin transporter gene
KW  - environment interaction
KW  - polymorphism
KW  - events
KW  - moderation
KW  - CB1 receptor antagonists
KW  - s allele
KW  - association
KW  - anxiety
KW  - metaanalysis
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143703
VL  - 10
IS  - 3
ER  - 
TY  - JOUR
A1  - Gutknecht, Lise
A1  - Popp, Sandy
A1  - Waider, Jonas
A1  - Sommerlandt, Frank M. J.
A1  - Göppner, Corinna
A1  - Post, Antonia
A1  - Reif, Andreas
A1  - van den Hove, Daniel
A1  - Strekalova, Tatyana
A1  - Schmitt, Angelika
A1  - Colaςo, Maria B. N.
A1  - Sommer, Claudia
A1  - Palme, Rupert
A1  - Lesch, Klaus-Peter
T1  - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice
JF  - Psychopharmacology
N2  - Rationale
While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation.

Objective
Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene.

Results
Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner.

Conclusions
Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
KW  - Serotonin
KW  - Tryptophan hydroxylase-2 (Tph2)
KW  - chronic stress
KW  - gene-by-environment interaction
KW  - anxiety
KW  - fear
KW  - depression
KW  - aggression
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586
VL  - 232
SP  - 2429
EP  - 2441
ER  -