Background: Recent studies have illuminated the diversity of roles for microRNAs in cellular, developmental, and pathophysiological processes. The study of microRNAs in human liver tissue promises to clarify the therapeutic and diagnostic value of this important regulatory mechanism of gene expression.Results: We conducted genome-wide profiling of microRNA expression in liver and performed an integrative analysis with previously collected genotype and transcriptome data. We report here that the Very Important Pharmacogenes (VIP Genes), comprising of genes of particular relevance for pharmacogenomics, are under substantial microRNA regulatory effect in the liver. We set out to elucidate the genetic basis of microRNA expression variation in liver and mapped microRNA expression to genomic loci as microRNA expression quantitative trait loci (miR-eQTLs). We identified common variants that attain genome-wide significant association (p < 10-10) with microRNA expression. We also found that the miR-eQTLs are significantly more likely to predict mRNA levels at a range of p-value thresholds than a random set of allele frequency matched SNPs, showing the functional effect of these loci on the transcriptome. Finally, we show that a large number of miR-eQTLs overlap with SNPs reproducibly associated with complex traits from the NHGRI repository of published genome-wide association studies as well as variants from a comprehensive catalog of manually curated pharmacogenetic associations.Conclusion: Our study provides important insights into the genomic architecture of gene regulation in a vital human organ, with important implications for our understanding of disease pathogenesis, therapeutic outcome, and other complex human phenotypes.
Bibliographical noteFunding Information:
This work was funded in part by PAAR (Pharmacogenomics of Anti-cancer Agents Research; U01 GM61393), Genotype-Tissue Expression project (GTeX) (R01 MH090937) and the Ralph W. and Grace M. Showalter Research Trust Award.
MiRNA expression was measured in 79 of the liver samples using the Exiqon miRCURY™ LNA Array v10.0 (for approximately 850 miRNAs) (Exiqon, Inc., Denmark). These 79 samples were a subset of the 206 liver tissue samples used for the mRNA expression profiling. The collection of samples from the Liver Tissue Cell Distribution System (funded by NIH #N01-DK-7-0004/ HHSN267200700004C and by the Cooperative Human Tissue Network) was approved by the institutional review boards (IRBs); The University of Chicago IRB also approved the use of the samples for the study described here.
- Human liver