title: Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence.
abstract: Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Mamdani
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Vernell
authors.initials: V
authors.lastname: Williamson
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Gowon O
authors.initials: GO
authors.lastname: McMichael
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Tana
authors.initials: T
authors.lastname: Blevins
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Fazil
authors.initials: F
authors.lastname: Aliev
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Adkins
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Hack
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Bigdeli
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: van der Vaart
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Bradley Todd
authors.initials: BT
authors.lastname: Web
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Department of Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, London SE5 8AF, United Kingdom.
authors.forename: Gursharan
authors.initials: G
authors.lastname: Kalsi
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Dick
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Brien P
authors.initials: BP
authors.lastname: Riley
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, VA, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dumur
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States of America; Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, United States of America; Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Vladimirov
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism*; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger