Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence
Year: 2015
Type: article
Study design: Observational Study
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.
Source: PLoS ONE
Authors: Mohammed Mamdani, Vernell Williamson, Gowon O. McMichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. van der Vaart, Bradley Todd Web, Silviu-Alin Bacanu, Gursharan Kalsi, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: State University of New York, Washington University in St. Louis, University of Connecticut, Johns Hopkins University, Virginia Commonwealth University, Texas Biomedical Research Institute, National Institutes of Health, SUNY Downstate Medical Center, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute
Awards: Genes, Environments & Interventions: Understanding and Addressing Alcohol Misuse, G1989832118, G2146332128, G2319812337, Using novel eQTL-based methods to find the molecular causes of alcohol dependency, Cross-species genetic analysis of ethanol-related behavior, Integrating miRNAs and mRNAs with alcohol eQTLs in two postmortem brain regions, G4503763930, JH/CIDR Genotyping for Genome-Wide Association Studies, G5960324223, Cross Species Characterization of Gene Networks in Acute Responses to Ethanol, G7093047072, G7522350138, G8267674335, Cross-species investigation of gene networks for ethanol-related behaviors, Brain Tissue Resource Center for Alcohol Research, ResearchTraining: Psychiatric and Statistical Genetics, Collaborative Study on the Genetics of Alcoholism (COGA).
OpenAlex ID: W2203621986