Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition.

乳腺癌全基因组关联研究（GWAS）已鉴定出150个基因组风险区域，其中包含13,000多个可靠的因果变异体（CCV）。CCV主要是非编码的，并且富含调控元件。然而，乳腺癌风险关联的潜在基因在很大程度上尚不清楚。在这里，我们使用遗传共定位分析来确定基因表达可能解释乳癌风险表型的基因座。使用来自乳腺癌协会协会（BCAC）和基因型组织表达（GTEx）项目和癌症基因组项目（TCGA）的数量性状基因位点（QTL）的数据，我们确定了共享的遗传关系，并揭示了癌症表型与癌症之间的新型关联。效应基因。十七个基因，包括NTN4被确定为潜在的乳腺癌风险介质。对于NTN4，我们显示rs61938093 CCV位于此区域，位于与NTN4启动子发生物理相互作用的增强子内，而风险等位基因降低了NTN4启动子的活性。此外，敲除乳腺细胞中的NTN4可增加体外细胞增殖和体内肿瘤生长。这些数据提供了将风险相关变异与可能导致乳腺癌易感性的基因相关联的证据。