The importance of TCF4 gene in the etiology of recurrent depressive disorders

Mossakowska-Wójcik, Joanna; Orzechowska, Agata; Talarowska, Monika; Szemraj, Janusz; Gałecki, Piotr

doi:10.1016/j.pnpbp.2017.03.014

Cited by 23 publications

(16 citation statements)

References 47 publications

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“…MEF2C was also included in ten of the 15 putative gene-sets identified for depression. The TCF4 gene coding region (Supplementary Figure 12) is also noteworthy as it contained two independently-associated variants for depression and has been identified in previous studies of depression 5, 9, 48 . TCF4 is involved in the synaptic plasticity 49 and the excitability of prefrontal neurons 50 and has been implicated in other psychiatric disorders 51 , including schizophrenia 34 .…”

Section: Discussionmentioning

confidence: 90%

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Howard

Adams

Clarke

et al. 2018

Preprint

350

628

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Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

show abstract

Section: Discussionmentioning

confidence: 90%

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Howard

Adams

Clarke

et al. 2018

Preprint

350

628

View full text Add to dashboard Cite

show abstract

“…MEF2C was also included in ten of the 15 putative gene-sets identified for depression. The TCF4 gene coding region (Supplementary Figure 12) is also noteworthy as it contained two independently-associated variants for depression and has been identified in previous studies of depression 5, 9, 29. TCF4 is involved in the excitability of prefrontal neurons 30 and has been implicated in other psychiatric disorders, including schizophrenia 21.…”

Section: Discussionmentioning

confidence: 93%

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

et al. 2019

View full text Add to dashboard Cite

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

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“…Rab3a is a synaptic protein that was shown to be suppressed in brain tissues from patients with major depressive disorder and stressed rats ( Kang et al, 2012 ). Tcf4 is implicated in the pathologies of recurrent depressive disorders ( Mossakowska-Wojcik et al, 2018 ). The depression etiology associated gene Cacnb4 ( Rouillard et al, 2016 ) is known as an important regulator of synapse density ( MacDonald et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Profiling and Co-expression Network Analysis of Learned Helplessness Regulated mRNAs and lncRNAs in the Mouse Hippocampus

Cao

et al. 2018

Front. Mol. Neurosci.

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Although studies provide insights into the neurobiology of stress and depression, the exact molecular mechanisms underlying their pathologies remain largely unknown. Long non-coding RNA (lncRNA) has been implicated in brain functions and behavior. A potential link between lncRNA and psychiatric disorders has been proposed. However, it remains undetermined whether IncRNA regulation, in the brain, contributes to stress or depression pathologies. In this study, we used a valid animal model of depression-like symptoms; namely learned helplessness, RNA-seq, Gene Ontology and co-expression network analyses to profile the expression pattern of lncRNA and mRNA in the hippocampus of mice. We identified 6346 differentially expressed transcripts. Among them, 340 lncRNAs and 3559 protein coding mRNAs were differentially expressed in helpless mice in comparison with control and/or non-helpless mice (inescapable stress resilient mice). Gene Ontology and pathway enrichment analyses indicated that induction of helplessness altered expression of mRNAs enriched in fundamental biological functions implicated in stress/depression neurobiology such as synaptic, metabolic, cell survival and proliferation, developmental and chromatin modification functions. To explore the possible regulatory roles of the altered lncRNAs, we constructed co-expression networks composed of the lncRNAs and mRNAs. Among our differentially expressed lncRNAs, 17% showed significant correlation with genes. Functional co-expression analysis linked the identified lncRNAs to several cellular mechanisms implicated in stress/depression neurobiology. Importantly, 57% of the identified regulatory lncRNAs significantly correlated with 18 different synapse-related functions. Thus, the current study identifies for the first time distinct groups of lncRNAs regulated by induction of learned helplessness in the mouse brain. Our results suggest that lncRNA-directed regulatory mechanisms might contribute to stress-induced pathologies; in particular, to inescapable stress-induced synaptic modifications.

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The importance of TCF4 gene in the etiology of recurrent depressive disorders

Cited by 23 publications

References 47 publications

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Profiling and Co-expression Network Analysis of Learned Helplessness Regulated mRNAs and lncRNAs in the Mouse Hippocampus

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