Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) 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 used pooled CRISPR activation and suppression screens to evaluate predicted GWAS target genes, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We performed 60 CRISPR screens and identified 21 genes predicted with high confidence to be GWAS targets that drive a cancer phenotype by driving a proliferation or DNA damage response in breast cells. We validated the regulation of a subset of these genes by BC-risk variants, and show the utility of expression profiling for drug repurposing. We provide a platform for identifying gene targets of risk variants, and present a blueprint of interventions for BC risk reduction and treatment.
