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) 已识别出 150 个基因组风险区域，其中包含超过 13,000 个可信的因果变异 (CCV)。 CCV 主要是非编码的并且富含调控元件。然而，与乳腺癌风险相关的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识别基因表达可能解释乳腺癌风险表型的位点。利用来自乳腺癌协会联盟 (BCAC) 的数据以及来自基因型组织表达 (GTEx) 项目和癌症基因组计划 (TCGA) 的数量性状位点 (QTL)，我们确定了共同的遗传关系，并揭示了癌症表型与癌症之间的新关联。效应基因。包括NTN4在内的 17 个基因被确定为乳腺癌风险的潜在介质。对于NTN4 ，我们发现该区域的rs61938093 CCV位于与NTN4启动子物理相互作用的增强子元件内，并且风险等位基因降低了NTN4启动子活性。此外，乳腺细胞中NTN4的敲低增加了体外细胞增殖和体内肿瘤生长。这些数据提供了证据，将风险相关变异与可能导致乳腺癌易感性的基因联系起来。