AbstractThe 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.