title: Significant impact of miRNA-target gene networks on genetics of human complex traits.
abstract: 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.
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Muramatsu
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Advanced Medicinal Research Laboratories, Tsukuba Research Institute, Ono Pharmaceutical CO., LTD., Tsukuba 300-4247, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Suita
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Laboratory for Disease Systems Modeling, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Eiryo
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH, UK.|Department of Haematology, University of Cambridge, Hills Rd, Cambridge CB2 0AH, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iotchkova
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH, UK.|Department of Haematology, University of Cambridge, Hills Rd, Cambridge CB2 0AH, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.|Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001827:Body Height / Q000235:genetics; D015536:Down-Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007668:Kidney / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D020412:Multifactorial Inheritance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D012306:Risk
chemical_list: C000605129:MIRN4728 microRNA, human; D035683:MicroRNAs; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases