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Enrichment Analysis Identifies Functional MicroRNA-Disease Associations in Humans.

Yuan D, Cui X, Wang Y, Zhao Y, Li H, Hu S, Chu X, Li Y, Li Q, Liu Q, Zhu W - PLoS ONE (2015)

Bottom Line: Further results suggest that filtering for miRNAs that target a greater number of disease-related genes (n ≥ 8) can significantly enrich for true MDAs from the set of putative associations (enrichment rate = 60.7%, adjusted hypergeometric p = 2.41×10-91).Considering the indirect effects of miRNAs further elevated the enrichment rate to 72.6%.By using this method, a novel MDA between miR-24 and ovarian cancer was found.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.

ABSTRACT
Substantial evidence has shown that microRNAs (miRNAs) may be causally linked to the occurrence and progression of human diseases. Herein, we conducted an enrichment analysis to identify potential functional miRNA-disease associations (MDAs) in humans by integrating currently known biological data: miRNA-target interactions (MTIs), protein-protein interactions, and gene-disease associations. Two contributing factors to functional miRNA-disease associations were quantitatively considered: the direct effects of miRNA that target disease-related genes, and indirect effects triggered by protein-protein interactions. Ninety-nine miRNAs were scanned for possible functional association with 2223 MeSH-defined human diseases. Each miRNA was experimentally validated to target ≥ 10 mRNA genes. Putative MDAs were identified when at least one MTI was confidently validated for a disease. Overall, 19648 putative MDAs were found, of which 10.0% was experimentally validated. Further results suggest that filtering for miRNAs that target a greater number of disease-related genes (n ≥ 8) can significantly enrich for true MDAs from the set of putative associations (enrichment rate = 60.7%, adjusted hypergeometric p = 2.41×10-91). Considering the indirect effects of miRNAs further elevated the enrichment rate to 72.6%. By using this method, a novel MDA between miR-24 and ovarian cancer was found. Compared with scramble miRNA overexpression of miR-24 was validated to remarkably induce ovarian cancer cells apoptosis. Our study provides novel insight into factors contributing to functional MDAs by integrating large quantities of previously generated biological data, and establishes a feasible method to identify plausible associations with high confidence.

No MeSH data available.


Related in: MedlinePlus

Average effect of direct and indirect interactions on enrichment of experimentally validated MDAs.(A) Increasing the number of miRNA-targeted DGs enriches for true MDAs. *** p < 0.001 versus ≥ 1; (B) Denser protein-protein association between miRNA-targeted NDGs and DGs tends to facilitate true MDAs. ** p < 0.01, *** p < 0.001 versus ≥ 0; (C and D) Effect on true MDA enrichment by co-consideration of both factors. ** p < 0.01, *** p < 0.001 versus the NmiRNA-targeted DGs ≥ 1 and PIS ≥ 0 group; NmiRNA-targeted DGs: the sum of DGs that are targeted by a given miRNA. MDA: miRNA-disease association; NDG: non-disease-related gene; DG: disease-related gene.
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pone.0136285.g002: Average effect of direct and indirect interactions on enrichment of experimentally validated MDAs.(A) Increasing the number of miRNA-targeted DGs enriches for true MDAs. *** p < 0.001 versus ≥ 1; (B) Denser protein-protein association between miRNA-targeted NDGs and DGs tends to facilitate true MDAs. ** p < 0.01, *** p < 0.001 versus ≥ 0; (C and D) Effect on true MDA enrichment by co-consideration of both factors. ** p < 0.01, *** p < 0.001 versus the NmiRNA-targeted DGs ≥ 1 and PIS ≥ 0 group; NmiRNA-targeted DGs: the sum of DGs that are targeted by a given miRNA. MDA: miRNA-disease association; NDG: non-disease-related gene; DG: disease-related gene.

Mentions: In this study, the direct effects factor assumed that each of the 19648 possible MDAs possessed at least one MTI. It was then investigated whether the number of MTIs could be used to identify true MDAs. This analysis revealed that miRNAs that target a greater number of DGs significantly increased the possibility that a given MDA may be real (Fig 2A, p < 0.001). This finding was confirmed after the entire set of 99 miRNAs was analyzed together (Fig 3A). Approximately two-thirds of the possible MDAs were assigned using only one MTI. Among them, only 616 MDAs were verified by experimental evidence in HMDD. In comparison, limiting the selection of putative MDAs to those that possessed a greater number of MTIs was effective in enriching for true MDAs. More than two-thirds of the real MDAs were assigned to those with ≥ 2 MTIs (n = 6185). Furthermore, if a strict threshold of ≥ 6 MTIs was used, experimental evidence in the HMDD database could be found for more than half of the MDAs (enrichment rate = 52.7%, hypergeometric adjusted p = 3.96×10−163). The MDAs with ≥ 10 MTIs are listed in S4 Table, of which 65.1% were validated by HMDD. Our findings suggest that the sum of diseased-related target genes may be an important contributing factor to functional MDAs.


Enrichment Analysis Identifies Functional MicroRNA-Disease Associations in Humans.

Yuan D, Cui X, Wang Y, Zhao Y, Li H, Hu S, Chu X, Li Y, Li Q, Liu Q, Zhu W - PLoS ONE (2015)

Average effect of direct and indirect interactions on enrichment of experimentally validated MDAs.(A) Increasing the number of miRNA-targeted DGs enriches for true MDAs. *** p < 0.001 versus ≥ 1; (B) Denser protein-protein association between miRNA-targeted NDGs and DGs tends to facilitate true MDAs. ** p < 0.01, *** p < 0.001 versus ≥ 0; (C and D) Effect on true MDA enrichment by co-consideration of both factors. ** p < 0.01, *** p < 0.001 versus the NmiRNA-targeted DGs ≥ 1 and PIS ≥ 0 group; NmiRNA-targeted DGs: the sum of DGs that are targeted by a given miRNA. MDA: miRNA-disease association; NDG: non-disease-related gene; DG: disease-related gene.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546424&req=5

pone.0136285.g002: Average effect of direct and indirect interactions on enrichment of experimentally validated MDAs.(A) Increasing the number of miRNA-targeted DGs enriches for true MDAs. *** p < 0.001 versus ≥ 1; (B) Denser protein-protein association between miRNA-targeted NDGs and DGs tends to facilitate true MDAs. ** p < 0.01, *** p < 0.001 versus ≥ 0; (C and D) Effect on true MDA enrichment by co-consideration of both factors. ** p < 0.01, *** p < 0.001 versus the NmiRNA-targeted DGs ≥ 1 and PIS ≥ 0 group; NmiRNA-targeted DGs: the sum of DGs that are targeted by a given miRNA. MDA: miRNA-disease association; NDG: non-disease-related gene; DG: disease-related gene.
Mentions: In this study, the direct effects factor assumed that each of the 19648 possible MDAs possessed at least one MTI. It was then investigated whether the number of MTIs could be used to identify true MDAs. This analysis revealed that miRNAs that target a greater number of DGs significantly increased the possibility that a given MDA may be real (Fig 2A, p < 0.001). This finding was confirmed after the entire set of 99 miRNAs was analyzed together (Fig 3A). Approximately two-thirds of the possible MDAs were assigned using only one MTI. Among them, only 616 MDAs were verified by experimental evidence in HMDD. In comparison, limiting the selection of putative MDAs to those that possessed a greater number of MTIs was effective in enriching for true MDAs. More than two-thirds of the real MDAs were assigned to those with ≥ 2 MTIs (n = 6185). Furthermore, if a strict threshold of ≥ 6 MTIs was used, experimental evidence in the HMDD database could be found for more than half of the MDAs (enrichment rate = 52.7%, hypergeometric adjusted p = 3.96×10−163). The MDAs with ≥ 10 MTIs are listed in S4 Table, of which 65.1% were validated by HMDD. Our findings suggest that the sum of diseased-related target genes may be an important contributing factor to functional MDAs.

Bottom Line: Further results suggest that filtering for miRNAs that target a greater number of disease-related genes (n ≥ 8) can significantly enrich for true MDAs from the set of putative associations (enrichment rate = 60.7%, adjusted hypergeometric p = 2.41×10-91).Considering the indirect effects of miRNAs further elevated the enrichment rate to 72.6%.By using this method, a novel MDA between miR-24 and ovarian cancer was found.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.

ABSTRACT
Substantial evidence has shown that microRNAs (miRNAs) may be causally linked to the occurrence and progression of human diseases. Herein, we conducted an enrichment analysis to identify potential functional miRNA-disease associations (MDAs) in humans by integrating currently known biological data: miRNA-target interactions (MTIs), protein-protein interactions, and gene-disease associations. Two contributing factors to functional miRNA-disease associations were quantitatively considered: the direct effects of miRNA that target disease-related genes, and indirect effects triggered by protein-protein interactions. Ninety-nine miRNAs were scanned for possible functional association with 2223 MeSH-defined human diseases. Each miRNA was experimentally validated to target ≥ 10 mRNA genes. Putative MDAs were identified when at least one MTI was confidently validated for a disease. Overall, 19648 putative MDAs were found, of which 10.0% was experimentally validated. Further results suggest that filtering for miRNAs that target a greater number of disease-related genes (n ≥ 8) can significantly enrich for true MDAs from the set of putative associations (enrichment rate = 60.7%, adjusted hypergeometric p = 2.41×10-91). Considering the indirect effects of miRNAs further elevated the enrichment rate to 72.6%. By using this method, a novel MDA between miR-24 and ovarian cancer was found. Compared with scramble miRNA overexpression of miR-24 was validated to remarkably induce ovarian cancer cells apoptosis. Our study provides novel insight into factors contributing to functional MDAs by integrating large quantities of previously generated biological data, and establishes a feasible method to identify plausible associations with high confidence.

No MeSH data available.


Related in: MedlinePlus