Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk.

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to -regulate the expression of genes. We hypothesise that -regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose , at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated -regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting -regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.