Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence
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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-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.
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Transcriptomes from complex tissues such as human brain may be organized into networks of co-expressed genes that better reflect the biological functions and organization of the tissue.
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From Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism (2019) · cites this paper as [8]
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- [109]Yan J, Aliev F Fau—Webb BT, Webb Bt Fau—Kendler KS, Kendler Ks Fau—Williamson VS, Williamson Vs Fau—Edenberg HJ, Edenberg Hj Fau—Agrawal A, et al Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. Addiction biology. 2014; 19(4): 708– 21. Epub Jan 30, 2013. D—NLM: NIHMS431520 [Available on 07/01/15] D—NLM: PMC3664249 [Available on 07/01/15] OTO—NOTNLM. 10.1111/adb.12035 23362995 PMC3664249 · DOI
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Cingiz, M. Ö., & Di̇ri̇, B. (2019) · Innovations in Intelligent Systems and Applications Conference (ASYU) · doi:10.1109/asyu48272.2019.8946426 · Cited by 1 · see citing works
Shi, X., Xu, B., He, T., Shi, J., & Zhang, L. (2024) · Research Square · doi:10.21203/rs.3.rs-4201908/v1 · Cited by 1 · see citing works
Genomic markers and psychological health outcomes of drinking behaviours in veterans
Turner, M. (2022) · Queensland University of Technology · doi:10.5204/thesis.eprints.235393
Yadav, P., Sibin, M. K., Pruthi, S. R., Yadav, A. K., Chatterjee, K., Chauhan, V. S., Sharma, N., & Panda, S. P. (2026) · Indian Journal of Psychiatry · doi:10.4103/indianjpsychiatry_1031_25
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- Authors
- Mamdani, M., Williamson, V., McMichael, G. O., Blevins, T., Aliev, F., Adkins, A., Hack, L., Bigdeli, T., D. van der Vaart, A., Web, B. T., Bacanu, S.-A., Kalsi, G., COGA Consortium, Kendler, K. S., Miles, M. F., Dick, D., Riley, B. P., Dumur, C., & Vladimirov, V. I.
- Affiliations
- Virginia Commonwealth University (US)
- Johns Hopkins University (US)
- Corresponding author
- Mamdani, Mohammed
- Vladimirov, Vladimir I.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-09-18
- Volume
- 10
- Issue
- 9
- Pages
- e0137671
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4575063
- OpenAlex
- W2203621986
- Cited by
- 73
- References
- 112
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 12 · 2020: 5 · 2019: 8 · 2018: 18 · 2017: 7 · 2016: 3
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Funders
- State University of New York
- Washington University in St. Louis
- University of Connecticut
- Johns Hopkins University (HHSN268200782096C, U01HG004438)
- Virginia Commonwealth University (P50 AA022537, K02AA018755, P20AA017828)
- Texas Biomedical Research Institute
- National Institutes of Health (HHSN268200782096C)
- SUNY Downstate Medical Center
- National Institute on Alcohol Abuse and Alcoholism (Grant U10AA008401, K02AA018755, R21AA022717, R01AA020634, R21AA022749, P20AA017828, VIVU10AA008401, P50AA022537, R28AA012725, U10AA008401)
- National Institute of Mental Health (T32MH020030)
- National Institute on Drug Abuse (Grant U10AA008401, HHSN268200782096C)
- National Human Genome Research Institute (U01HG004438, HHSN268200782096C)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- alcoholism, nucleus accumbens, gene co-expression network, microRNA, mRNA expression, cis-eQTL, hub genes, oxidative phosphorylation, mitochondrial dysfunction, MAPK signaling, cytokine signaling, alcohol use disorder genetics, CoGa
- MeSH terms
- Alcoholism, Astrocytes, Female, Humans, Male, Middle Aged, Neurons, Nucleus Accumbens, RNA, Messenger, Signal Transduction, Up-Regulation, Gene Expression Profiling, MicroRNAs, Quantitative Trait Loci, Gene Regulatory Networks, Transcriptome
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