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Molecular Evidence for a Dimensional Basis of Depression

ABSTRACT: Here we identified a set of genes with frequent expression changes in the postmortem brain of MDD subjectsand show that this gene set is genetically related to brain and organ illnesses frequently associated with MDD. Specifically, we performed a meta-analysis of eight gene array studies in three corticolimbic brain regions and identified ~450 genes frequentlyderegulated in MDD (n=103 subjects, 50.5%MDD). These “MetaA-MDD” genes includepreviously-implicated neuroplasticity- and stress-related genes (CRH, BDNF, VGF), encompass multiple synaptic and signaling pathways, and suggests complex changes in cell structure and function. MetaA-MDD genes display low connectivity andhubnessin coexpression networks andare evenly distributed throughout the genome. However, MetaA-MDD genesare significantly over-represented in gene sets identified by the genome-wide association studies for brain disorders and organ diseases sharing clinical co-morbidity with MDD (e.g., cardiovascular, metabolic syndrome), but not for other diseases or body functions. Together, this study describes a robustmolecular characterization of altered brain function in MDD, and provides evidence for a shared genetic structure linking MDD andrelated illnesses, together biologically defining abroader dimensional definition ofa depressive-like syndrome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44593 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA190603

REPOSITORIES: GEO

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Molecular Evidence for a Dimensional Basis of Depression

Project description:Here we identified a set of genes with frequent expression changes in the postmortem brain of MDD subjectsand show that this gene set is genetically related to brain and organ illnesses frequently associated with MDD. Specifically, we performed a meta-analysis of eight gene array studies in three corticolimbic brain regions and identified ~450 genes frequentlyderegulated in MDD (n=103 subjects, 50.5%MDD). These âMetaA-MDDâ genes includepreviously-implicated neuroplasticity- and stress-related genes (CRH, BDNF, VGF), encompass multiple synaptic and signaling pathways, and suggests complex changes in cell structure and function. MetaA-MDD genes display low connectivity andhubnessin coexpression networks andare evenly distributed throughout the genome. However, MetaA-MDD genesare significantly over-represented in gene sets identified by the genome-wide association studies for brain disorders and organ diseases sharing clinical co-morbidity with MDD (e.g., cardiovascular, metabolic syndrome), but not for other diseases or body functions. Together, this study describes a robustmolecular characterization of altered brain function in MDD, and provides evidence for a shared genetic structure linking MDD andrelated illnesses, together biologically defining abroader dimensional definition ofa depressive-like syndrome. 14 pairs of human postmotem AMY samples of MDD patients and control

2016-07-03 | E-GEOD-44593 | biostudies-arrayexpress

Cell-Specific Transcriptomic Analysis of CRH+ cells Identifies Unique Cellular Responses to Chronic Stress

Project description:Rationale: A previous transcriptome meta-analysis revealed significantly lower levels of corticotropin-releasing hormone (CRH) mRNA in corticolimbic brain regions in major depressive disorder (MDD) subjects. Rodent studies show that cortical CRH is mostly expressed in GABAergic neurons; however, the characteristic features of CRH+ cells in human brain cortex and their association with MDD are largely unknown. Methods: Subgenual anterior cingulate cortex (sgACC) of human subjects without brain disorders were labeled using fluorescent in situ hybridization (FISH) for CRH and markers of excitatory (SLC17A7), inhibitory (GAD1) neurons, as well as markers of other interneuron subpopulations (PVALB, SST, VIP). MDD-associated changes in CRH+ cell density and cellular CRH expression (n=6/group) were analyzed. RNA-sequencing was performed on sgACC CRH+ neurons from comparison and MDD subjects (n=6/group), and analyzed for group differences. Results: About 80% of CRH+ cells were GABAergic and 17.5% were glutamatergic. CRH+ GABAergic neurons co-expressed VIP (52%), SST (7%), or PVALB (7%). MDD subjects displayed lower CRH mRNA levels in GABAergic neurons relative to comparison subjects without changes in cell density. CRH+ neurons show transcriptomic profile suggesting lower excitability and less GABA release and reuptake. Further analyses suggested that these molecular changes are not mediated by altered glucocorticoid feedback and potentially occur downstream for a common modulator of neurotrophic function. Summary: CRH+ cells in human sgACC are a heterogeneous population of GABAergic neurons, although largely co-expressing VIP. MDD is associated with reduced markers of inhibitory function of CRH+ neurons.

2022-02-22 | GSE193417 | GEO

Expression data from human brain anterior cingulate cortex - including control samples and samples with major depression disorders (20 samples MD2_ACC)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 20 total samples in 10 pairs were analyzed in postmortem tissue from the anterior cingulate cortex.

2014-05-16 | E-GEOD-54562 | biostudies-arrayexpress

Expression data from human brain anterior cingulate cortex - including control samples and samples with major depression disorders (50 samples MD3_ACC)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 50 total samples in 25 pairs were analyzed in postmortem tissue from the anterior cingulate cortex.

2014-05-16 | E-GEOD-54563 | biostudies-arrayexpress

Expression data from human brain amygdala - including control samples and samples with major depression disorders (42 samples MD3_AMY)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 42 total samples in 21 pairs were analyzed in postmortem tissue from the amygdala.

2014-05-16 | E-GEOD-54564 | biostudies-arrayexpress

Expression data from human brain anterior cingulate cortex - including control samples and samples with major depression disorders (32 samples MD1_ACC)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 32 total samples in 16 pairs were analyzed in postmortem tissue from the anterior cingulate cortex.

2014-05-16 | E-GEOD-54565 | biostudies-arrayexpress

Expression data from human brain dorsolateral prefrontal cortex - including control samples and samples with major depression disorders (30 samples BA9_F)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 30 total samples in 15 pairs were analyzed in postmortem tissue from the dorsolateral prefrontal cortex.

2014-05-16 | E-GEOD-54568 | biostudies-arrayexpress

Expression data from human brain dorsolateral prefrontal cortex - including control samples and samples with major depression disorders (26 samples NY_BA9)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 26 total samples in 13 pairs were analyzed in postmortem tissue from the dorsolateral prefrontal cortex.

2014-05-16 | E-GEOD-54570 | biostudies-arrayexpress

Expression data from human brain amygdala - including control samples and samples with major depression disorders (28 samples MD1_AMY)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 28 total samples in 14 pairs were analyzed in postmortem tissue from the amygdala.

2014-05-16 | E-GEOD-54566 | biostudies-arrayexpress

Expression data from human brain dorsolateral prefrontal cortex - including control samples and samples with major depression disorders (28 samples BA9_M)

Project description:Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases (See publication for details). 28 total samples in 14 pairs were analyzed in postmortem tissue from the dorsolateral prefrontal cortex.

2014-05-16 | E-GEOD-54567 | biostudies-arrayexpress

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