A Conserved BDNF, Glutamate- and GABA-Enriched Gene Module Related to Human Depression Identified by Coexpression Meta-Analysis and DNA Variant Genome-Wide Association Studies
Identifieur interne : 000291 ( France/Analysis ); précédent : 000290; suivant : 000292A Conserved BDNF, Glutamate- and GABA-Enriched Gene Module Related to Human Depression Identified by Coexpression Meta-Analysis and DNA Variant Genome-Wide Association Studies
Auteurs : Lun-Ching Chang [États-Unis] ; Stephane Jamain [France] ; Chien-Wei Lin [États-Unis] ; Dan Rujescu [Allemagne] ; George C. Tseng [États-Unis] ; Etienne Sibille [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Adulte d'âge moyen, Analyse de profil d'expression de gènes, Encéphale (métabolisme), Encéphale (physiopathologie), Facteur neurotrophique dérivé du cerveau (génétique), Facteur neurotrophique dérivé du cerveau (métabolisme), Famille des récepteurs Eph (génétique), Famille des récepteurs Eph (métabolisme), Famille multigénique, Femelle, Génome humain, Humains, Molécules d'adhérence cellulaire neuronale (génétique), Molécules d'adhérence cellulaire neuronale (métabolisme), Mâle, Protéines de la matrice extracellulaire (génétique), Protéines de la matrice extracellulaire (métabolisme), Protéines de tissu nerveux (génétique), Protéines de tissu nerveux (métabolisme), Prédisposition génétique à une maladie, Récepteurs GABA (génétique), Récepteurs GABA (métabolisme), Récepteurs métabotropes au glutamate (génétique), Récepteurs métabotropes au glutamate (métabolisme), Régulation de l'expression des gènes, Réseaux de régulation génique, Serine endopeptidases (génétique), Serine endopeptidases (métabolisme), Sujet âgé, Transcriptome, Trouble dépressif majeur (génétique), Trouble dépressif majeur (métabolisme), Trouble dépressif majeur (physiopathologie), Voies et réseaux métaboliques (génétique), Étude d'association pangénomique, Études cas-témoins.
- MESH :
- génétique : Facteur neurotrophique dérivé du cerveau, Famille des récepteurs Eph, Molécules d'adhérence cellulaire neuronale, Protéines de la matrice extracellulaire, Protéines de tissu nerveux, Récepteurs GABA, Récepteurs métabotropes au glutamate, Serine endopeptidases, Trouble dépressif majeur, Voies et réseaux métaboliques.
- métabolisme : Encéphale, Facteur neurotrophique dérivé du cerveau, Famille des récepteurs Eph, Molécules d'adhérence cellulaire neuronale, Protéines de la matrice extracellulaire, Protéines de tissu nerveux, Récepteurs GABA, Récepteurs métabotropes au glutamate, Serine endopeptidases, Trouble dépressif majeur.
- physiopathologie : Encéphale, Trouble dépressif majeur.
- Adulte d'âge moyen, Analyse de profil d'expression de gènes, Famille multigénique, Femelle, Génome humain, Humains, Mâle, Prédisposition génétique à une maladie, Régulation de l'expression des gènes, Réseaux de régulation génique, Sujet âgé, Transcriptome, Étude d'association pangénomique, Études cas-témoins.
English descriptors
- KwdEn :
- Aged, Brain (metabolism), Brain (physiopathology), Brain-Derived Neurotrophic Factor (genetics), Brain-Derived Neurotrophic Factor (metabolism), Case-Control Studies, Cell Adhesion Molecules, Neuronal (genetics), Cell Adhesion Molecules, Neuronal (metabolism), Depressive Disorder, Major (genetics), Depressive Disorder, Major (metabolism), Depressive Disorder, Major (physiopathology), Extracellular Matrix Proteins (genetics), Extracellular Matrix Proteins (metabolism), Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways (genetics), Middle Aged, Multigene Family, Nerve Tissue Proteins (genetics), Nerve Tissue Proteins (metabolism), Receptors, Eph Family (genetics), Receptors, Eph Family (metabolism), Receptors, GABA (genetics), Receptors, GABA (metabolism), Receptors, Metabotropic Glutamate (genetics), Receptors, Metabotropic Glutamate (metabolism), Serine Endopeptidases (genetics), Serine Endopeptidases (metabolism), Transcriptome.
- MESH :
- chemical , genetics : Brain-Derived Neurotrophic Factor, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Nerve Tissue Proteins, Receptors, Eph Family, Receptors, GABA, Receptors, Metabotropic Glutamate, Serine Endopeptidases.
- genetics : Depressive Disorder, Major, Metabolic Networks and Pathways.
- metabolism : Brain, Brain-Derived Neurotrophic Factor, Cell Adhesion Molecules, Neuronal, Depressive Disorder, Major, Extracellular Matrix Proteins, Nerve Tissue Proteins, Receptors, Eph Family, Receptors, GABA, Receptors, Metabotropic Glutamate, Serine Endopeptidases.
- physiopathology : Brain, Depressive Disorder, Major.
- Aged, Case-Control Studies, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Multigene Family, Transcriptome.
Abstract
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. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.
Url:
DOI: 10.1371/journal.pone.0090980
PubMed: 24608543
PubMed Central: 3946570
Affiliations:
- Allemagne, France, États-Unis
- Pennsylvanie, Île-de-France
- Créteil, Pittsburgh
- Université de Pittsburgh
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PMC:3946570Le document en format XML
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<term>Études cas-témoins</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Brain-Derived Neurotrophic Factor</term>
<term>Cell Adhesion Molecules, Neuronal</term>
<term>Extracellular Matrix Proteins</term>
<term>Nerve Tissue Proteins</term>
<term>Receptors, Eph Family</term>
<term>Receptors, GABA</term>
<term>Receptors, Metabotropic Glutamate</term>
<term>Serine Endopeptidases</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Depressive Disorder, Major</term>
<term>Metabolic Networks and Pathways</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur neurotrophique dérivé du cerveau</term>
<term>Famille des récepteurs Eph</term>
<term>Molécules d'adhérence cellulaire neuronale</term>
<term>Protéines de la matrice extracellulaire</term>
<term>Protéines de tissu nerveux</term>
<term>Récepteurs GABA</term>
<term>Récepteurs métabotropes au glutamate</term>
<term>Serine endopeptidases</term>
<term>Trouble dépressif majeur</term>
<term>Voies et réseaux métaboliques</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term>
<term>Brain-Derived Neurotrophic Factor</term>
<term>Cell Adhesion Molecules, Neuronal</term>
<term>Depressive Disorder, Major</term>
<term>Extracellular Matrix Proteins</term>
<term>Nerve Tissue Proteins</term>
<term>Receptors, Eph Family</term>
<term>Receptors, GABA</term>
<term>Receptors, Metabotropic Glutamate</term>
<term>Serine Endopeptidases</term>
</keywords>
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<term>Facteur neurotrophique dérivé du cerveau</term>
<term>Famille des récepteurs Eph</term>
<term>Molécules d'adhérence cellulaire neuronale</term>
<term>Protéines de la matrice extracellulaire</term>
<term>Protéines de tissu nerveux</term>
<term>Récepteurs GABA</term>
<term>Récepteurs métabotropes au glutamate</term>
<term>Serine endopeptidases</term>
<term>Trouble dépressif majeur</term>
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<keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Encéphale</term>
<term>Trouble dépressif majeur</term>
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<keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Brain</term>
<term>Depressive Disorder, Major</term>
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<keywords scheme="MESH" xml:lang="en"><term>Aged</term>
<term>Case-Control Studies</term>
<term>Female</term>
<term>Gene Expression Profiling</term>
<term>Gene Expression Regulation</term>
<term>Gene Regulatory Networks</term>
<term>Genetic Predisposition to Disease</term>
<term>Genome, Human</term>
<term>Genome-Wide Association Study</term>
<term>Humans</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Multigene Family</term>
<term>Transcriptome</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Adulte d'âge moyen</term>
<term>Analyse de profil d'expression de gènes</term>
<term>Famille multigénique</term>
<term>Femelle</term>
<term>Génome humain</term>
<term>Humains</term>
<term>Mâle</term>
<term>Prédisposition génétique à une maladie</term>
<term>Régulation de l'expression des gènes</term>
<term>Réseaux de régulation génique</term>
<term>Sujet âgé</term>
<term>Transcriptome</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
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<front><div type="abstract" xml:lang="en"><p>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. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.</p>
</div>
</front>
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<author><name sortKey="Eisch, Aj" uniqKey="Eisch A">AJ Eisch</name>
</author>
<author><name sortKey="Gold, Sj" uniqKey="Gold S">SJ Gold</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Duman, Rs" uniqKey="Duman R">RS Duman</name>
</author>
<author><name sortKey="Monteggia, Lm" uniqKey="Monteggia L">LM Monteggia</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rajkowska, G" uniqKey="Rajkowska G">G Rajkowska</name>
</author>
<author><name sortKey="O Wyer, G" uniqKey="O Wyer G">G O’Dwyer</name>
</author>
<author><name sortKey="Teleki, Z" uniqKey="Teleki Z">Z Teleki</name>
</author>
<author><name sortKey="Stockmeier, Ca" uniqKey="Stockmeier C">CA Stockmeier</name>
</author>
<author><name sortKey="Miguel Hidalgo, Jj" uniqKey="Miguel Hidalgo J">JJ Miguel-Hidalgo</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Pennsylvanie</li>
<li>Île-de-France</li>
</region>
<settlement><li>Créteil</li>
<li>Pittsburgh</li>
</settlement>
<orgName><li>Université de Pittsburgh</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Chang, Lun Ching" sort="Chang, Lun Ching" uniqKey="Chang L" first="Lun-Ching" last="Chang">Lun-Ching Chang</name>
</region>
<name sortKey="Lin, Chien Wei" sort="Lin, Chien Wei" uniqKey="Lin C" first="Chien-Wei" last="Lin">Chien-Wei Lin</name>
<name sortKey="Sibille, Etienne" sort="Sibille, Etienne" uniqKey="Sibille E" first="Etienne" last="Sibille">Etienne Sibille</name>
<name sortKey="Tseng, George C" sort="Tseng, George C" uniqKey="Tseng G" first="George C." last="Tseng">George C. Tseng</name>
<name sortKey="Tseng, George C" sort="Tseng, George C" uniqKey="Tseng G" first="George C." last="Tseng">George C. Tseng</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Jamain, Stephane" sort="Jamain, Stephane" uniqKey="Jamain S" first="Stephane" last="Jamain">Stephane Jamain</name>
</region>
<name sortKey="Jamain, Stephane" sort="Jamain, Stephane" uniqKey="Jamain S" first="Stephane" last="Jamain">Stephane Jamain</name>
<name sortKey="Jamain, Stephane" sort="Jamain, Stephane" uniqKey="Jamain S" first="Stephane" last="Jamain">Stephane Jamain</name>
</country>
<country name="Allemagne"><noRegion><name sortKey="Rujescu, Dan" sort="Rujescu, Dan" uniqKey="Rujescu D" first="Dan" last="Rujescu">Dan Rujescu</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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