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MicroRNAs (miRNA) are key modulators of gene expression and so act as putative fine-tuners of complex phenotypes. Here, we hypothesized that causal variants of complex traits are enriched in miRNAs and miRNA-target networks. First, we conducted a genome-wide association study (GWAS) for seven functional and milk production traits using imputed sequence variants (13~15 million) and >10,000 animals from three dairy cattle breeds,  i . e ., Holstein (HOL), Nordic red cattle (RDC) and Jersey (JER). Second, we analyzed for enrichments of association signals in miRNAs and their miRNA-target networks. Our results demonstrated that genomic regions harboring miRNA genes were significantly (P < 0.05) enriched with GWAS signals for milk production traits and mastitis, and that enrichments within miRNA-target gene networks were significantly higher than in random gene-sets for the majority of traits. Furthermore, most between-trait and across-breed correlations of enrichments with miRNA-target networks were significantly greater than with random gene-sets, suggesting pleiotropic effects of miRNAs. Intriguingly, genes that were differentially expressed in response to mammary gland infections were significantly enriched in the miRNA-target networks associated with mastitis. All these findings were consistent across three breeds. Collectively, our observations demonstrate the importance of miRNAs and their targets for the expression of complex traits.

MicroRNA-guided prioritization of genome-wide association signals reveals the importance of microRNA-target gene networks for complex traits in cattle