Abstract
Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet the target genes in these loci remain largely unknown. To address this knowledge gap, we conducted a series of multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We developed and validated ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation, using genomic and transcriptomic data from normal breast tissue samples of 652 females of African, Asian, or European ancestry. These models were then applied to GWAS data of 178,534 breast cancer cases and 248,300 controls from these ancestry groups for association analyses. We identified 290 genes associated with breast cancer risk, including 103 previously unreported in TWAS and 46 located at least 500Kb away from any previously identified risk variants. Among them, 39 genes exhibited distinct associations with breast cancer risk by estrogen receptor status. The identified genes were enriched in pathways related to homologous recombination, apoptosis, p53, PI3K/AKT/mTOR, estrogen, and IL-2/STAT5 signaling. Single-cell RNA sequencing and in vitro experiment data provided additional functional evidence for 169 genes. Our study uncovered large numbers of candidate breast cancer susceptibility genes and contributed valuable insights into the genetics and biology of this common cancer.