Genome-wide identification of miRNAs associated with alcoholism endophenotypes

Innate sensitivity to ethanol can be an important first step towards understanding alcohol use disorders. We investigated miRNA-modulated transcriptional expression in brain associated with a predisposition to the hypnotic effect of ethanol, as measured by Loss of Righting Reflex (LORR). Expression of miRNAs and mRNAs in brain were independently analyzed for an association with LORR in mice from the LXS recombinant inbred panel. These results were then integrated via a meta-analysis for miRNA-mRNA target pairs identified in miRNA target interaction databases. We found 112 significant miRNA-mRNA pairs where a large majority of miRNAs and mRNAs were highly inter-connected. Most pairs indicated a pattern of increased levels of miRNAs and reduced levels of mRNAs being associated with more alcohol sensitive strains. For example, CaMKIIn1 was targeted by multiple miRNAs associated with LORR. CAMK2N1 is an inhibitor of CAMK2, which among other functions, phosphorylates or binds to GABAA and NMDA receptors. Our results suggest a novel role of miRNA-mediated regulation of an inhibitor of CAMK2 and its downstream targets including the GABAA and NMDA receptors, which have been previously implicated to have a role in ethanol-induced sedation and sensitivity. This dataset includes small RNA NGS sequencing data from 12 ILS/IbgTejJ and ISS/IbgTejJ mouse RNA samples. Six mice (3 from each strain) were saline treated (SAL) 8 hours before tissue extraction. The remaining 6 were untreated (NVE). The saline-treated mouse samples were provided by Richard Radcliffe and the naive samples were provided by Boris Tabakoff. All analysis was done by the Kechris Group