Alcohol use disorder (AUD) is a complex genetic trait with important biological, behavioral and socioeconomic components. AUD genetic studies have implicated multiple loci; however, with the exception of alcohol metabolizing enzymes, these genetic results are inconclusive. Therefore, integration of human postmortem brain gene expression data with genetic data offers an opportunity to complement these genetic studies to better understand disease etiology. Furthermore, postmortem studies of human alcoholics have shown that transcriptional changes are associated with the disorder. The current expression studies in AUD have exclusively targeted mRNA expression differences, while miRNAs, very important modulators of mRNA expression levels, have been largely unexplored. Of the few miRNA studies in AUD postmortem brains, as well as in animal and cell based models, miRNAs have been shown to be involved in disease etiology. In this proposal we attempt to complement and expand on earlier expression studies by 1) detecting disease specific miRNA and mRNA expression differences in a larger AUD sample (N=82) than previously assessed, 2) assessing these miRNA and mRNA expression differences within two brain regions (PFC and NAc) with important function in alcohol addiction, 3) determining the specific neuronal and glial contributions to the genome wide expression profile detected in whole brain and, finally, 4) integrating the differential expression profiles with GWAS data of AUD subjects to detect alcohol response eQTLs.
MiRNAs are key regulators of gene regulation and are implicated in neuropsychiatric disorders, including alcohol and drug addiction. This proposal aims to 1) detect differentially expressed miRNA and mRNA in two postmortem AUD brain regions: PFC and NAc, 2) estimate neuronal and glial specific contributions to disease development and 3) identify regulatory genetic loci affecting expression of the disease relevant miRNAs and mRNAs we detect.
| Edwards, Alexis C; Heron, Jon; Vladimirov, Vladimir et al. (2017) The Rate of Change in Alcohol Misuse Across Adolescence is Heritable. Alcohol Clin Exp Res 41:57-64 |
| Adkins, Amy E; Hack, Laura M; Bigdeli, Tim B et al. (2017) Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms. Alcohol Clin Exp Res 41:911-928 |
| Nalluri, Joseph J; Rana, Pratip; Barh, Debmalya et al. (2017) Determining causal miRNAs and their signaling cascade in diseases using an influence diffusion model. Sci Rep 7:8133 |
| Mamdani, Mohammed; Williamson, Vernell; McMichael, Gowon O et al. (2015) Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence. PLoS One 10:e0137671 |
