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Open Access Highly Accessed Research article

The regulatory effect of miRNAs is a heritable genetic trait in humans

Paul Geeleher1, Stephanie R Huang2, Eric R Gamazon3, Aaron Golden4 and Cathal Seoighe15*

Author Affiliations

1 Department of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland

2 Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, USA

3 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, USA

4 Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA

5 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa

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BMC Genomics 2012, 13:383  doi:10.1186/1471-2164-13-383

Published: 10 August 2012

Abstract

Background

microRNAs (miRNAs) have been shown to regulate the expression of a large number of genes and play key roles in many biological processes. Several previous studies have quantified the inhibitory effect of a miRNA indirectly by considering the expression levels of genes that are predicted to be targeted by the miRNA and this approach has been shown to be robust to the choice of prediction algorithm. Given a gene expression dataset, Cheng et al. defined the regulatory effect score (RE-score) of a miRNA as the difference in the gene expression rank of targets of the miRNA compared to non-targeted genes.

Results

Using microarray data from parent-offspring trios from the International HapMap project, we show that the RE-score of most miRNAs is correlated between parents and offspring and, thus, inter-individual variation in RE-score has a genetic component in humans. Indeed, the mean RE-score across miRNAs is correlated between parents and offspring, suggesting genetic differences in the overall efficiency of the miRNA biogenesis pathway between individuals. To explore the genetics of this quantitative trait further, we carried out a genome-wide association study of the mean RE-score separately in two HapMap populations (CEU and YRI). No genome-wide significant associations were discovered; however, a SNP rs17409624, in an intron of DROSHA, was significantly associated with mean RE-score in the CEU population following permutation-based control for multiple testing based on all SNPs mapped to the canonical miRNA biogenesis pathway; of 244 individual miRNA RE-scores assessed in the CEU, 214 were associated (p < 0.05) with rs17409624. The SNP was also nominally significantly associated (p = 0.04) with mean RE-score in the YRI population. Interestingly, the same SNP was associated with 17 (8.5% of all expressed) miRNA expression levels in the CEU. We also show here that the expression of the targets of most miRNAs is more highly correlated with global changes in miRNA regulatory effect than with the expression of the miRNA itself.

Conclusions

We present evidence that miRNA regulatory effect is a heritable trait in humans and that a polymorphism of the DROSHA gene contributes to the observed inter-individual differences.