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. PLoS One 2014;9(3):e90980
Date
03/13/2014Pubmed ID
24608543Pubmed Central ID
PMC3946570DOI
10.1371/journal.pone.0090980Scopus ID
2-s2.0-84897414615 (requires institutional sign-in at Scopus site) 77 CitationsAbstract
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.
Author List
Chang LC, Jamain S, Lin CW, Rujescu D, Tseng GC, Sibille EAuthor
Chien-Wei Lin PhD Associate Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedBrain
Brain-Derived Neurotrophic Factor
Case-Control Studies
Cell Adhesion Molecules, Neuronal
Depressive Disorder, Major
Extracellular Matrix Proteins
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
Middle Aged
Multigene Family
Nerve Tissue Proteins
Receptors, Eph Family
Receptors, GABA
Receptors, Metabotropic Glutamate
Serine Endopeptidases
Transcriptome
