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PLoS Genet. 2018 Dec 17;14(12):e1007837. doi: 10.1371/journal.pgen.1007837. [Epub ahead of print]

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

Wilk G1,2, Braun R2,3.

Author information

1
Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois, United States of America.
2
Biostatistics Division, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
3
Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America.

Abstract

Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with trait diversity and disease susceptibility, yet their functional properties often remain 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 several studies have predicted the location of SNPs in miRNA binding sites, to date there has been no comprehensive analysis of their impact on miRNA regulation. 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 on dysregulated pathways are responsible for miRNA dysregulation of individual genes in tumors. Using an integrative regression analysis that incorporates miRNA expression, mRNA expression, and SNP genotype data, we identify functional SNPs that we term "regulatory QTLs (regQTLs)": loci whose alleles impact the regulation of genes by miRNAs. We apply the method to breast, liver, lung, and prostate cancer data from The Cancer Genome Atlas, and provide a tool to explore the findings.

PMID:
30557297
DOI:
10.1371/journal.pgen.1007837
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Conflict of interest statement

The authors have declared that no competing interests exist.

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