Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, 80045, CO, USA.
Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 80045, CO, USA.
BMC Genomics. 2018 Aug 29;19(1):639. doi: 10.1186/s12864-018-5004-3.
MicroRNAs (miRNAs) are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation. There is increasing evidence of miRNAs playing an important role in alcohol related disorders. However, the role of miRNAs as mediators of the genetic effect on alcohol phenotypes is not fully understood. We conducted a high-throughput sequencing study to measure miRNA expression levels in alcohol naïve animals in the LXS panel of recombinant inbred (RI) mouse strains. We then combined the sequencing data with genotype data, microarry gene expression data, and data on alcohol-related behavioral phenotypes such as 'Drinking in the dark', 'Sleep time', and 'Low dose activation' from the same RI panel. SNP-miRNA-gene triplets with strong association within the triplet that were also associated with one of the 4 alcohol phenotypes were selected and a Bayesian network analysis was used to aggregate results into a directed network model.
We found several triplets with strong association within the triplet that were also associated with one of the alcohol phenotypes. The Bayesian network analysis found two networks where a miRNA mediates the genetic effect on the alcohol phenotype. The miRNAs were found to influence the expression of protein-coding genes, which in turn influences the quantitative phenotypes. The pathways in which these genes are enriched have been previously associated with alcohol-related traits.
This work enhances association studies by identifying miRNAs that may be mediating the association between genetic markers (SNPs) and the alcohol phenotypes. It suggests a mechanism of how genetic variants are affecting traits of interest through the modification of miRNA expression.
微小 RNA（miRNA）是一种小的非编码 RNA，可以与信使 RNA 结合并促进其降解或抑制其翻译。越来越多的证据表明 miRNA 在酒精相关疾病中发挥着重要作用。然而，miRNA 作为遗传效应与酒精表型之间的中介物的作用尚未完全了解。我们进行了一项高通量测序研究，以测量 LXS 面板中的重组近交（RI）小鼠品系中酒精-naive 动物的 miRNA 表达水平。然后，我们将测序数据与基因型数据、微阵列基因表达数据以及来自同一 RI 面板的酒精相关行为表型（如“暗饮”、“睡眠时间”和“低剂量激活”）的数据相结合。选择在三元组内具有强关联的 SNP-miRNA-基因三元组，并且与 4 种酒精表型之一相关联，然后使用贝叶斯网络分析将结果聚合到有向网络模型中。
我们发现了几个在三元组内具有强关联的三元组，并且与其中一个酒精表型相关联。贝叶斯网络分析发现了两个网络，其中 miRNA 介导了遗传效应对酒精表型的影响。发现 miRNA 影响了蛋白质编码基因的表达，进而影响了定量表型。这些基因富集的途径以前与酒精相关特征有关。
这项工作通过识别可能介导遗传标记（SNP）与酒精表型之间关联的 miRNA，增强了关联研究。它提出了一种遗传变异如何通过修饰 miRNA 表达来影响感兴趣的特征的机制。
