Genome-wide association study combined with biological context can reveal more disease-related SNPs altering microRNA target seed sites

Abstract

BackgroundEmerging studies demonstrate that single nucleotide polymorphisms (SNPs) resided in the microRNA recognition element seed sites (MRESSs) in 3′UTR of mRNAs are putative biomarkers for human diseases and cancers. However, exhaustively experimental validation for the causality of MRESS SNPs is impractical. Therefore bioinformatics have been introduced to predict causal MRESS SNPs. Genome-wide association study (GWAS) provides a way to detect susceptibility of millions of SNPs simultaneously by taking linkage disequilibrium (LD) into account, but the multiple-testing corrections implemented to suppress false positive rate always sacrificed the sensitivity. In our study, we proposed a method to identify candidate causal MRESS SNPs from 12 GWAS datasets without performing multiple-testing corrections. Alternatively, we used biological context to ensure credibility of the selected SNPs.ResultsIn 11 out of the 12 GWAS datasets, MRESS SNPs were over-represented in SNPs with p-value ≤ 0.05 (odds ratio (OR) ranged from 1.1 to 2.4). Moreover, host genes of susceptible MRESS SNPs in each of the 11 GWAS dataset shared biological context with reported causal genes. There were 286 MRESS SNPs identified by our method, while only 13 SNPs were identified by multiple-testing corrections with a given threshold of 1 × 10−5, which is a common cutoff used in GWAS. 27 out of the 286 candidate SNPs have been reported to be deleterious while only 2 out of 13 multiple-testing corrected SNPs were documented in PubMed. MicroRNA-mRNA interactions affected by the 286 candidate SNPs were likely to present negatively correlated expression. These SNPs introduced greater alternation of binding free energy than other MRESS SNPs, especially when grouping by haplotypes (4210 vs. 4105 cal/mol by mean, 9781 vs. 8521 cal/mol by mean, respectively).ConclusionsMRESS SNPs are promising disease biomarkers in multiple GWAS datasets. The method of integrating GWAS p-value and biological context is stable and effective for selecting candidate causal MRESS SNPs, it reduces the loss of sensitivity compared to multiple-testing corrections. The 286 candidate causal MRESS SNPs provide researchers a credible source to initialize their design of experimental validations in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-669) contains supplementary material, which is available to authorized users.

MicroRNA gene polymorphisms and the risk of colorectal cancer

“…Previous findings showed that human miRNAs with single-nucleotide polymorphisms (SNPs) can be targets of genetic variation in human genomic DNA sequences and may be related to susceptibility of human disease ( 20 ). miRNA SNPs have inter-individual differences in disease diagnosis, treatment, and prognosis.…”

Impact of miRNA-binding site polymorphisms in STAT3 gene on occurrence and clinical characteristics of systemic lupus erythematosus

“…In a study aiming to search the SNPs resided in the miRNA recognition element seed sites (MRESSs) in several GWAS datasets, it was proposed that rs1053005 and rs1053023 polymorphisms affect the function of miR-4793 and miR-4506/4640, respectively. 27 In Figure 1, we summarized the effects of these polymorphisms on the function of potential predicted miRNAs, leading to upregulation of STAT3 and finally SLE pathogenesis via increased inflammatory cytokines and autoantibody production.…”

“…These two common polymorphisms have been suggested to affect the thermodynamic features and secondary structure of STAT3 3 0 -UTR and consequently the miRNA binding capacity of multiple miRNAs. 27,28 These polymorphisms can finally influence the expression of STAT3 and modulate the risk of SLE development. In the current study, we aimed to assess the plausible association between rs1053005 and rs1053023 and the susceptibility to SLE disease in the Iranian population.…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…MicroRNAs achieve their biological function by binding to mature mRNAs and in most cases, decreasing the expression level of target mRNAs (26). The association between microRNA and human disease can be converted into an association between microRNA-mRNA interaction and human disease, thereby providing a means to influence microRNA-regulated human diseases (27). There is accumulating evidence indicating a significant miRNA contribution to depression, anxiety, and antidepressant action (28,29).…”