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Significant Impact Of MiRNA–target Gene Networks On Genetics Of Human Complex Traits

Y. Okada, T. Muramatsu, Naomasa Suita, M. Kanai, E. Kawakami, V. Iotchkova, N. Soranzo, J. Inazawa, T. Tanaka
Published 2016 · Biology, Medicine

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The impact of microRNA (miRNA) on the genetics of human complex traits, especially in the context of miRNA-target gene networks, has not been fully assessed. Here, we developed a novel analytical method, MIGWAS, to comprehensively evaluate enrichment of genome-wide association study (GWAS) signals in miRNA–target gene networks. We applied the method to the GWAS results of the 18 human complex traits from >1.75 million subjects, and identified significant enrichment in rheumatoid arthritis (RA), kidney function, and adult height (P < 0.05/18 = 0.0028, most significant enrichment in RA with P = 1.7 × 10−4). Interestingly, these results were consistent with current literature-based knowledge of the traits on miRNA obtained through the NCBI PubMed database search (adjusted P = 0.024). Our method provided a list of miRNA and target gene pairs with excess genetic association signals, part of which included drug target genes. We identified a miRNA (miR-4728-5p) that downregulates PADI2, a novel RA risk gene considered as a promising therapeutic target (rs761426, adjusted P = 2.3 × 10−9). Our study indicated the significant impact of miRNA–target gene networks on the genetics of human complex traits, and provided resources which should contribute to drug discovery and nucleic acid medicine.
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