Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders

Darby, Miranda M.; Yolken, Robert H.; Sabunciyan, Sarven

doi:10.1038/tp.2016.173

Cited by 63 publications

(43 citation statements)

References 72 publications

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“…Importantly, among the top co-dysregulated processes involved in resiliency/susceptibility to depression was the ribosome. It has also been observed from work on postmortem brains of individuals with major psychiatric disorders that protein synthesis, essentially through dysregulation of ribosomal genes and messenger RNA processing, was a pathway of central importance to psychiatric health (Darby et al, 2016). Our own results are convergent with these findings, with the addition of ubiquitin-mediated proteolysis (Figures 3C, 5C), that has also been previously regarded as crucial in the antidepressant treatment response in both mice and humans (Park et al, 2017).…”

Section: Discussionsupporting

confidence: 88%

Translational identification of transcriptional signatures of major depression and antidepressant response

Hervé¹,

Bergon²,

Guisquet³

et al. 2017

European Neuropsychopharmacology

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Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD.

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Section: Discussionsupporting

confidence: 88%

Translational identification of transcriptional signatures of major depression and antidepressant response

Hervé¹,

Bergon²,

Guisquet³

et al. 2017

European Neuropsychopharmacology

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“…Consistent with this, literature data reported the presence of elevated FKBP5 mRNA levels in cortical regions in psychiatric disorders patients, including BPD subjects [48, 49]. Further, it was evidenced how stress often precedes depressive episodes in BPD [16].…”

Section: Discussionsupporting

confidence: 66%

<b><i>FKBP5</i></b> Gene Variants May Modulate Depressive Features in Bipolar Disorder

et al. 2019

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Background: Previous evidence suggested the possible association of FK506 binding protein 5 (FKBP5) gene variants in bipolar disorder (BPD). Objective: Given the need of refinement of the findings obtained in large but poorly phenotyped samples, this study investigated the possible role of variants within FKBP5 in a small but deeply phenotyped BPD sample. Methods: A sample (N = 131) of bipolar patients were investigated with 10 polymorphisms within the FKBP5 gene. A control sample (N = 65) was also used for the analyses. Treatment response and remission of symptoms were evaluated using of the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Young Mania Rating Scale (YMRS). The same analyses were also performed on the depressive subsample of BPD (D.BPD). Results: rs3800373 was associated with disorder risk in the depressive BPD subsample with the G allele being more frequent in subjects with a D.BPD phenotype. This was the only association that survived statistical correction. Conclusions: rs3800373 FKBP5 may increase the risk of developing predominantly depressed BPD, probably through the creation of an enhancer consensus sequence in the 3′UTR of the gene, thus potentially increasing its expression. This finding seems to be partially supported by literature data, which evidenced increased levels of FKBP5 in psychiatric subjects.

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“…Changes in the expression of Wnt pathway components are associated with several neuronal disorders including schizophrenia, bipolar disorder, Alzheimer's disease, and autism [63]. Similarly, the dysregulation of ribosome biogenesis has been implicated in neuropsychiatric disorders in previous studies of postmortem brains [64,65], olfactory neurosphere derived cells [66], and neural progenitor cells [67]. Another enriched gene ontology category, damaged DNA binding, is also known to play a key role in neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 98%

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Zhang

et al. 2019

Preprint

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Heterozygous deletions in the 15q13.3 region are associated with several neuropsychiatric disorders including autism, schizophrenia, and attention deficit hyperactivity disorder. Several genes within the 15q13.3 deletion region may play a role in neuronal dysfunction, based on association studies in humans and functional studies in mice, but the intermediate molecular mechanisms remain unknown.We analyzed the genome-wide effects of the 15q13.3 microdeletion on the transcriptome and epigenome. Induced pluripotent stem cell (iPSC) lines from three patients with the typical heterozygous 15q13.3 microdeletion and three sex-matched controls were generated and converted into induced neurons (iNs) using the neurogenin-2 induction method. We analyzed genome-wide gene expression using RNA-Seq, genome-wide DNA methylation using SeqCap-Epi, and genome-wide chromatin accessibility using ATAC-Seq, in both iPSCs and iNs. In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the deletion on the transcriptome and epigenome, with the effects being cell type specific and occurring at discrete loci. Several genes and pathways associated with neuropsychiatric disorders and neuronal development were significantly altered, including Wnt signaling, ribosome biogenesis, DNA binding, and clustered protocadherins. This molecular systems analysis of a large neuropsychiatric microdeletion can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders. IntroductionThe neuropsychiatric 15q13.3 microdeletion (OMIM 612001) is a heterozygous deletion of approximately 1.5-2 Mb at coordinates 30.5 Mb to 32.5 Mb on chromosome 15 (hg19) [1]. The deletion breakpoints lie within two regions of segmental duplications, which likely mediate the creation of the recurrent microdeletion via non-allelic homologous recombination [2]. The 15q13.3 microdeletion has an estimated prevalence of 1 in 40,000 individuals, and was first reported in 2008, in nine individuals with mental retardation, seizures, and mild facial dysmorphism [3]. Since then, several other phenotypes have been associated with this copy number variant (CNV), including autism spectrum disorder, schizophrenia, mood disorders, attention deficit hyperactivity disorder, hypotonia, and cardiac defects [1,4,5].The most common form of the 15q13.3 microdeletion, which is the subject of our study, results in the heterozygous loss of seven protein-coding genes (CHRNA7, FAN1, TRPM1, KLF13, OTUD7A, MTMR10, ARHGAP11B) and one microRNA (MIR211) [4]. Several of these genes have previously been investigated as candidates for having a role in the neuropsychiatric symptoms associated with the CNV. The most frequently proposed candidate gene is C...

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Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders

Cited by 63 publications

References 72 publications

Translational identification of transcriptional signatures of major depression and antidepressant response

Translational identification of transcriptional signatures of major depression and antidepressant response

<b><i>FKBP5</i></b> Gene Variants May Modulate Depressive Features in Bipolar Disorder

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

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