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The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P<5.82×10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
Breast cancer is the most common malignancy among women in many countries1. Genetic factors play an important role in its etiology2-5. Since 2007, genome-wide association studies (GWAS) have identified approximately 170 genetic loci harboring common, low-penetrance variants for breast cancer6-13, but these variants explain less than 20% of familial relative risk7. Most disease-associated risk variants identified by GWAS are located in non-protein-coding regions and are not in linkage disequilibrium with any nonsynonymous coding SNPs14. Many of these susceptibility variants are located in gene regulatory elements15,16, and it has been hypothesized that many GWAS-identified associations may be driven by the regulatory function of risk variants on the expression of nearby genes. For breast cancer, recent studies have already shown that GWAS-identified associations at more than 15 loci are likely due to the effect of risk variants at these loci on regulating the expression of either nearby or more distal genes7,9,10,13,17-22. However, for the large majority of the GWAS-identified breast cancer risk loci, the genes responsible for the associations remain unknown.
Several studies have reported that regulatory variants may account for a large proportion of disease heritability not yet discovered through GWAS23-25. Many of these variants may have a small effect size, and thus are difficult to identify in individual SNP-based GWAS, even with a large sample size. Applying gene-based approaches that aggregate the...