Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

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Keywords breast cancer subtype, causal gene, GWAS, TWAS
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Journal Genetic Epidemiology
Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J, Abu-full, Z. (Zomoroda), … Jiang, X. (Xia). (2020). Transcriptome-wide association study of breast cancer risk by estrogen-receptor status. Genetic Epidemiology. doi:10.1002/gepi.22288