Germline Allelic Expression of Genes at 17q22 Locus Associates with Risk of Breast Cancer

A bstract Translation of GWAS findings into preventive approaches is challenged by identifying the causal risk variants and understanding their biological mechanisms. We present a novel approach using AE ratios to perform quantitative case-control analysis to identify risk associations, causal regulatory variants, and target genes. Using the breast cancer risk locus 17q22 to validate this approach, we found a significant shift in the AE patterns of STXBP4 (rs2628315) and COX11 (rs17817901) in the normal breast tissue of cases and healthy controls. Preferential expression of the G-rs2628315 and A-rs17817901 alleles, more often observed in cases, was associated with an increased risk for breast cancer. Analysis of blood samples from cases and controls found a similar association. Furthermore, we identified two putative cis -regulatory variants – rs17817901 and rs8066588 – that affect a miRNA and a transcription factor binding site, respectively. Our work reveals the power of integrating AE data in cancer risk studies and presents a novel approach to identifying risk - case-control association analysis using AE ratios.