title: 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.
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.
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Lun-Ching
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Inserm U955, Psychiatrie Génétique, Créteil, France; Université Paris Est, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Jamain
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Psychiatry, Center For Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; D000091042:Reelin Protein; C579455:BDNF protein, human; D036081:Receptors, Eph Family; C000717127:RELN protein, human; D012697:Serine Endopeptidases