Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence

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, V. Hesselbrock, H. J. EdenbergJ. Nurnberger, T. Foroud, S. Kuperman, J. Kramer, B. Porjesz, L. Bierut, A. Goate, J. Rice, K. Bucholz, M. Schuckit, J. Tischfield, L. Almasy, R. Taylor, D. Dick, L. Bauer, D. Koller, S. O'Connor, L. Wetherill, X. Xuei, Grace Chan, S. Kang, N. Manz, M. Rangaswamy, J. Rohrbaugh, J. C. Wang, A. Brooks, F. Aliev, A. Parsian, M. Reilly

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    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-typespecific 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.

    Idioma originalEnglish (US)
    Número de artículoe0137671
    PublicaciónPloS one
    EstadoPublished - sept 18 2015

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