基因组关联研究(GWAS)已经发现了200多个与乳腺癌风险相关的位点。大部分候选致病变异体位于非编码区域，可能通过调节基因表达来调节癌症风险。然而，在解释和转化GWAS结果方面，确定关联的确切目标以及识别它介导的表型是一个重大挑战。在这里，我们展示了混合CRISPR筛选在识别GWAS靶基因和定义它介导的癌症表型方面非常有效。通过CRISPR介导的基因激活或抑制，我们测量了在2D、3D和免疫缺陷小鼠中增殖的效果以及对DNA修复的影响。我们进行了60项CRISPR筛选，并确定了20个高度自信预测为GWAS靶标的基因，这些基因通过推动增殖或调节乳腺细胞DNA损伤反应来促进癌症。我们验证了这些基因中的一部分被乳腺癌风险变异体调控的结论。我们展示了表型CRISPR筛选可以准确地确定风险位点的基因靶标。除了定义与乳腺癌风险增加有关的风险位点的基因靶标外，我们还提供了一个平台，用于确定由风险变异介导的基因靶标和表型。©2023.作者。

Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in non-coding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS.Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants.We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.© 2023. The Author(s).