Background Understanding gene regulation is important but difficult. Elucidating tissue-specific gene regulation mechanism is even more challenging and requires gene co-expression network assembled from protein–protein interaction, transcription factor and gene binding, and post-transcriptional regulation (e.g., miRNA targeting) information. The miRNA binding affinity could therefore be changed by SNP(s) located at the 3′ untranslated regions (3′UTR) of the target messenger RNA (mRNA) which miRNA(s) interacts with. Genome-wide association study (GWAS) has reported significant numbers of loci hosting SNPs associated with many traits. The goal of this study is to pinpoint GWAS functional variants located in 3′UTRs and elucidate if the genes harboring these variants along with their targeting miRNAs are associated with genetic traits relevant to certain tissues. Methods By applying MIGWAS, CoCoNet, ANNOVAR, and DAVID bioinformatics software and utilizing the gene expression database (e.g. GTEx data) to study GWAS summary statistics for 43 traits from 28 GWAS studies, we have identified a list of miRNAs and targeted genes harboring 3′UTR variants, which could contribute to trait-relevant tissue over miRNA-target gene network. Results Our result demonstrated that strong association between traits and tissues exists, and in particular, the Primary Biliary Cirrhosis (PBC) trait has the most significant p-value for all 180 tissues among all 43 traits used for this study. We reported SNPs located in 3′UTR regions of genes (SFMBT2, ZC3HAV1, and UGT3A1) targeted by miRNAs for PBC trait and its tissue association network. After employing Gene Ontology (GO) analysis for PBC trait, we have also identified a very important miRNA targeted gene over miRNA-target gene network, PFKL, which encodes the liver subunit of an enzyme. Conclusions The non-coding variants identified from GWAS studies are casually assumed to be not critical to translated protein product. However, 3′ untranslated regions (3′UTRs) of genes harbor variants can often change the binding affinity of targeting miRNAs playing important roles in protein translation degree. Our study has shown that GWAS variants could play important roles on miRNA-target gene networks by contributing the association between traits and tissues. Our analysis expands our knowledge on trait-relevant tissue network and paves way for future human disease studies.

Background Genome-wide association studies (GWAS) have uncovered thousands of genetic variants that are associated with complex human traits and diseases. miRNAs are single-stranded non-coding RNAs. In particular, genetic variants located in the 3’UTR region of mRNAs may play an important role in gene regulation through their interaction with miRNAs. Existing studies have not been thoroughly conducted to elucidate 3’UTR variants discovered through GWAS. The goal of this study is to analyze patterns of GWAS functional variants located in 3’UTRs about their relevance in the network between hosting genes and targeting miRNAs, and elucidate the association between the genes harboring these variants and genetic traits. Methods We employed MIGWAS, ANNOVAR, MEME, and DAVID software packages to annotate the variants obtained from GWAS for 31 traits and elucidate the association between their harboring genes and their related traits. We identified variants that occurred in the motif regions that may be functionally important in affecting miRNA binding. We also conducted pathway analysis and functional annotation on miRNA targeted genes harboring 3’UTR variants for a trait with the highest percentage of 3’UTR variants occurring. Results The Child Obesity trait has the highest percentage of 3’UTR variants (75%). Of the 16 genes related to the Child Obesity trait, 5 genes (ETV7, GMEB1, NFIX, ZNF566, ZBTB40) had a significant association with the term DNA-Binding (p < 0.05). EQTL analysis revealed 2 relevant tissues and 10 targeted genes associated with the Child Obesity trait. In addition, Red Blood Cells (RBC), Hemoglobin (HB), and Package Cell Volume (PCV) have overlapping variants. In particular, the PIM1 variant occurred inside the HB Motif region 37,174,641–37,174,660, and LUC7L3 variant occurred inside RBC Motif region 50,753,918–50,753,937. Conclusion Variants located in 3’UTR can alter the binding affinity of miRNA and impact gene regulation, thus warranting further annotation and analysis. We have developed a bioinformatics bash pipeline to automatically annotate variants, determine the number of variants in different categories for each given trait, and check common variants across different traits. This is a valuable tool to annotate a large number of GWAS result files.