Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate .

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, , we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a enhancer element, consistent with the function of as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another enhancer element, was negatively correlated with looping of this element to the promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.