Predictive modeling of miRNA-mediated predisposition to alcohol-related phenotypes in mouse
Pratyaydipta Rudra1, Wen J Shi2, Pamela Russell3
1Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, 80045, CO, USA. pratyaydipta.rudra@ucdenver.edu.
Background:
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.
Results:
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.
Conclusion:
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.
Insights
MicroRNAs (miRNAs) mediate genetic effects on alcohol phenotypes by influencing gene expression. This study identifies specific miRNAs and pathways involved in alcohol-related traits, offering insights into genetic mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression.
- Emerging evidence links miRNAs to alcohol-related disorders.
- The precise role of miRNAs in mediating genetic influences on alcohol phenotypes remains unclear.
Purpose of the Study:
- To investigate the role of miRNAs as mediators of genetic effects on alcohol-related phenotypes.
- To identify specific miRNAs and genetic pathways associated with alcohol behaviors.
- To elucidate the mechanism by which genetic variants impact alcohol-related traits via miRNA expression.
Main Methods:
- High-throughput sequencing of miRNA expression in an LXS recombinant inbred (RI) mouse panel.
- Integration of miRNA sequencing data with genotype, gene expression, and alcohol phenotype data.
- Bayesian network analysis to model SNP-miRNA-gene interactions and identify mediating pathways.
Main Results:
- Identified significant SNP-miRNA-gene triplets associated with alcohol phenotypes.
- Discovered two networks where miRNAs mediate genetic effects on alcohol phenotypes.
- Found that miRNAs influence protein-coding gene expression, impacting quantitative traits enriched in alcohol-related pathways.
Conclusions:
- This study enhances association studies by pinpointing miRNAs that mediate the link between genetic markers and alcohol phenotypes.
- Provides a mechanistic understanding of how genetic variations affect traits through altered miRNA expression.
- Highlights the potential of miRNAs as therapeutic targets for alcohol-related disorders.
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