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

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dc.contributor.authorGeeleher, Paulen_ZA
dc.contributor.authorHuang, Stephanieen_ZA
dc.contributor.authorGamazon, Ericen_ZA
dc.contributor.authorGolden, Aaronen_ZA
dc.contributor.authorSeoighe, Cathalen_ZA
dc.date.accessioned2015-11-18T03:58:45Z
dc.date.available2015-11-18T03:58:45Z
dc.date.issued2012en_ZA
dc.description.abstractBACKGROUND: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.en_ZA
dc.identifier.apacitationGeeleher, P., Huang, S., Gamazon, E., Golden, A., & Seoighe, C. (2012). The regulatory effect of miRNAs is a heritable genetic trait in humans. <i>BMC Genomics</i>, http://hdl.handle.net/11427/15081en_ZA
dc.identifier.chicagocitationGeeleher, Paul, Stephanie Huang, Eric Gamazon, Aaron Golden, and Cathal Seoighe "The regulatory effect of miRNAs is a heritable genetic trait in humans." <i>BMC Genomics</i> (2012) http://hdl.handle.net/11427/15081en_ZA
dc.identifier.citationGeeleher, P., Huang, S. R., Gamazon, E. R., Golden, A., & Seoighe, C. (2012). The regulatory effect of miRNAs is a heritable genetic trait in humans. BMC genomics, 13(1), 383.en_ZA
dc.identifier.ris TY - Journal Article AU - Geeleher, Paul AU - Huang, Stephanie AU - Gamazon, Eric AU - Golden, Aaron AU - Seoighe, Cathal AB - 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. DA - 2012 DB - OpenUCT DO - 10.1186/1471-2164-13-383 DP - University of Cape Town J1 - BMC Genomics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2012 T1 - The regulatory effect of miRNAs is a heritable genetic trait in humans TI - The regulatory effect of miRNAs is a heritable genetic trait in humans UR - http://hdl.handle.net/11427/15081 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15081
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2164-13-383
dc.identifier.vancouvercitationGeeleher P, Huang S, Gamazon E, Golden A, Seoighe C. The regulatory effect of miRNAs is a heritable genetic trait in humans. BMC Genomics. 2012; http://hdl.handle.net/11427/15081.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2012 Geeleher et al.; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceBMC Genomicsen_ZA
dc.source.urihttp://www.biomedcentral.com/bmcgenomics/en_ZA
dc.subject.othermicroRNAs (miRNAs)en_ZA
dc.subject.otherinhibitory effecten_ZA
dc.subject.otherregulatory effect score (RE-score)en_ZA
dc.titleThe regulatory effect of miRNAs is a heritable genetic trait in humansen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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