Abstract
Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either disrupt a miRNA binding site or create a new miRNA binding site can affect the allele-specific expression of target genes. By integrating public expression quantitative trait locus (eQTL) data, miRNA binding site predictions, small RNA sequencing, and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets, we identified genetic variants that can affect gene expression by modulating miRNA binding efficiency. We also identified MRE-SNPs located in regions associated with complex traits, indicating possible causative mechanisms associated with these loci. The results of this study expand the current understanding of gene expression regulation and help to interpret the mechanisms underlying eQTL effects.
Highlights
Recent genome-wide association studies (GWAS) have identified susceptibility loci for a large number of complex diseases and traits
Mapping studies of genetic variants associated with individual differences in gene expression levels have revealed that the expression of most genes is influenced by multiple loci [2,3] and that signals identified by GWAS are enriched for expression quantitative trait locus (eQTL) [4]
To identify all SNPs that are in linkage disequilibrium (LD) with cis-eQTL SNPs, we identified proxies with absolute LD (R2 = 1, 1000G pilot 1 reference panel for CEU population) and their minor allele frequencies using the SNAP v2.2 webtool [26]
Summary
Recent genome-wide association studies (GWAS) have identified susceptibility loci for a large number of complex diseases and traits. Mapping studies of genetic variants associated with individual differences in gene expression levels (expression QTLs or eQTLs) have revealed that the expression of most genes is influenced by multiple loci [2,3] and that signals identified by GWAS are enriched for eQTLs [4]. MicroRNAs (miRNA) are small endogenous noncoding RNAs that modulate gene expression at the post-transcriptional level. They bind to specific sequence motifs called miRNA response elements (MREs) in the 30 untranslated region (3' UTR) of mRNAs, repressing the activity of their targets by affecting mRNA stability and/or protein translation. Recent studies have indicated that these two mechanisms are tightly coupled and PLOS ONE | DOI:10.1371/journal.pone.0141351 October 23, 2015
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