The CREB1-BDNF-NTRK2 Pathway in Depression: Multiple Gene-Cognition-Environment Interactions

Juhász, Gabriella; Dunham, Jason S.; McKie, Shane; Thomas, E. J.; Downey, Darragh; Chase, Diana; Lloyd-Williams, Kathryn; Tóth, Zoltán; Platt, Hazel; Mekli, Krisztina; Payton, Antony; Elliott, Richard M.; Williams, Steve; Anderson, Ian M.; Deakin, Bill

doi:10.1016/j.biopsych.2010.11.019

Cited by 140 publications

(151 citation statements)

References 74 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…BDNF mediates activity-dependent neuroplasticity in the hippocampus and cortex, which is critical to the adaptation of environmental stress and also contribute to antidepressant effects (77,100,101). It is interesting to note that our previous study demonstrated that genetic variation in the CREB1-BDNF-NTRK2 pathway also interacts with childhood adversity to increase risk of depression (102).…”

Section: Discussionmentioning

confidence: 90%

“…For example, we used self-reported questionnaires to measure lifetime depression, depressive and anxiety symptoms, and negative life events that, although proven and widely used, might be influenced by recall bias. Therefore, we validated them in a subpopulation of 142 during face-to-face interviews showing good reliability (102,103). In addition, we did not control for the timing of depression and life events.…”

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%

“…Three stress-related phenotypic outcome variables were analyzed. Reported lifetime depression was derived from targeted questions of a self-reported questionnaire and was validated in a subpopulation during face-to-face diagnostic interviews (102). To measure current depression and anxiety we used the Brief Symptom Inventory (106) anxiety and depression subscales with additional items for depression.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The background questionnaire collected information about socio‐demographic data, personal and family psychiatric history. Sex, age, ethnicity, reported migraine and reported lifetime depression data were derived from this validated questionnaire (Juhasz et al 2011). …”

Section: Methodsmentioning

confidence: 99%

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Juhász

Csépány

Magyar

et al. 2016

Genes Brain and Behavior

View full text Add to dashboard Cite

One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross‐sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID‐Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 × RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression‐ and anxiety‐related phenotypes. In addition, a Bayesian systems‐based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone.

show abstract

Biological Models of Unipolar Depression

Cleare

Rane

2013

The Wiley‐Blackwell Handbook of Mood Disorders

View full text Add to dashboard Cite

The CREB1-BDNF-NTRK2 Pathway in Depression: Multiple Gene-Cognition-Environment Interactions

Cited by 140 publications

References 74 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

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Biological Models of Unipolar Depression

Contact Info

Product

Resources

About