New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype

Lazáry, Judit; Lazáry, Áron; Gonda, Xénia; Benko, Anita; Molnár, Eszter; Juhász, Gabriella; Bagdy, György

doi:10.1016/j.biopsych.2008.03.030

Cited by 89 publications

(64 citation statements)

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“…The paradigmatic example of a candidate gene interacting with recent negative life events and childhood adversity is the serotonin transporter gene (SLC6A4). This gene has a functional polymorphism in the promoter region (5-HTTLPR) (62), whose risk variant is associated with a 50% reduction in serotonin transporter protein and predisposition to depression after negative life events (63)(64)(65), although there are negative studies. In our study we used this gene as a benchmark and reference for the Bayesian analysis to allow the comparison of posterior probabilities of relevance.…”

Section: Discussionmentioning

confidence: 99%

“…Data of all eligible participants were included in the analysis, regardless of reported psychiatric disorders ( Table 1). Details of the recruitment strategy and the population cohorts can be read in previous publications (64,102,103). In short, we recruited participants aged between 18-60 y from Greater Manchester, United Kingdom through general practices, advertisements, and a Web site, and from Budapest, Hungary, through general practices and advertisements.…”

Section: Methodsmentioning

confidence: 99%

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Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.galanin receptors | mood disorders | network-based analysis | neurogenesis | transmitter coexistence M ajor depressive disorder (MDD) is a common and serious disease afflicting more women than men, and a leading cause of disability worldwide, associated with much suffering and major costs for society (1, 2). Environmental psychosocial stressors are important in pathogenesis, because episodes are usually preceded by adverse life events, and early childhood experiences of physical and emotional abuse and parental neglect are important vulnerability factors (3, 4). Genetic vulnerability is significant with a heritability of about 35% (5). We remain ignorant about the brain processes that translate these genetic and environmental influences into depressive symptoms or risk. A major clue is that effective antidepressant drugs act directly or indirectly to enhance neurotransmission in serotonin (5-HT) and norepinephrine monoamine pathways, proving the monoamine hypothesis of depression (6-8). Many other candidate mechanisms have been identified in anatomical, pharmacological, and behavioral studies of stress in rodents. However, the demonstration of stateor trait-related abnormalities in human monoamine or other neural systems remains frustratingly elusive, despite modern brain-imaging methods. To determine whether the neuropeptide galanin has a role in depression, we used a unique Bayesian systems-based analysis to dissect out the influ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The less active short allele of the 5HTTLPR is associated with higher neuroticism (Greenberg et al, 2000) and it affects both the structure and function of an endophenotypic corticolimbic circuit underpinning emotion regulation (Hariri et al, 2006). Although the 5HTTLPR polymorphism accounts for only a few percent of the variation in neuroticism, it nevertheless shares the characteristic of increasing sensitivity to life events in triggering depression (Caspi et al, 2003;Jacobs et al, 2006;Uher and McGuffin, 2008;Lazary et al, 2008). The fact that CNR1 variants are not only associated with neuroticism but also interact with recent life events to predict current depressive symptoms suggests the variants act on the core endophenotypic emotion regulation processes of neuroticism.…”

Section: Discussionmentioning

confidence: 99%

CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

Juhász

Chase

Pegg

et al. 2009

Neuropsychopharmacol

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Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n ¼ 1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5 0 end of the CNR1 gene significantly interacts with the 3 0 end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene Â environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression--and probably also for co-morbid psychiatric conditions such as substance use disorders--through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.

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“…With regard to these findings, the main genetic axis associated with depression is related to alleles of the serotonin gene that participate in the serotonin synthesis and transport cascade, where the presence of one or more copies of the short allele (5-HTTLPR) in the promoter region of the gene (5-HTT) represents the strongest risk factor for the disorder [22][23][24][25][26][27][28]. The 5-HTT alleles are related to the formation of the transmembrane that activates the serotonin reuptake in the pre-synaptic cell, and the 5-HTTLPR polymorphism is associated with decreased response to antidepressants [29].…”

Section: Genetic Correlationsmentioning

confidence: 99%

Depression Across the Species

Dias¹,

Santos²,

Takeuchi³

et al. 2009

TOPJ

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Backgrounds: this article has two close related goals. First it reviews the current literature on animal models of depression, using data mining techniques. Second it discusses whether it is feasible or not to extend the concept of depression to non-humans. Results: the use of animal models of depression increased dramatically over the last years, in association with the development of new drugs and genetic studies. On the other hand, the possibility to assume a strong correlation between human depression and low mood in other mammals remains unfeasible. Human depression represents a 'reaching-point', both at the organic and the phenomenological levels; nosographically, it can be asserted only within the horizon of possibilities represented by alternative disorders with which it shares common features.

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New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype

Cited by 89 publications

References 38 publications

Brain galanin system genes interact with life stresses in depression-related phenotypes

Brain galanin system genes interact with life stresses in depression-related phenotypes

CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

Depression Across the Species

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