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Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors

Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with trait diversity and disease susceptibility, yet the functional properties of many genetic variants and their molecular interactions remains unclear. It has been hypothesized that SNPs in microRNA binding sites may disrupt gene regulation by microRNAs (miRNAs), short non-coding RNAs that bind to mRNA and downregulate the target gene. While a number of studies have been conducted to predict the location of SNPs in miRNA binding sites, to date there has been no comprehensive analysis of how SNP variants may impact miRNA regulation of genes. Here we investigate the functional properties of genetic variants and their effects on miRNA regulation of gene expression in cancer. Our analysis is motivated by the hypothesis that distinct alleles may cause differential binding (from miRNAs to mRNAs or from transcription factors to DNA) and change the expression of genes. We previously identified pathways--systems of genes conferring specific cell functions--that are dysregulated by miRNAs in cancer, by comparing miRNA-pathway associations between healthy and tumor tissue. We draw on these results as a starting point to assess whether SNPs in genes on dysregulated pathways are responsible for miRNA dysregulation of individual genes in tumors. Using an integrative analysis that incorporates miRNA expression, mRNA expression, and SNP genotype data, we identify SNPs that appear to influence the association between miRNAs and genes, which we term "regulatory QTLs (regQTLs)": loci whose alleles impact the regulation of genes by miRNAs. We describe the method, apply it to analyze four cancer types (breast, liver, lung, prostate) using data from The Cancer Genome Atlas (TCGA), and provide a tool to explore the findings.

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