Genome-wide association studies (GWAS) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWAS) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify novel candidate genes, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 47 tissues from the Genotype-Tissue Expression data using a multivariate adaptive shrinkage method along with association summary statistics from the Breast Cancer Association Consortium and UK Biobank data. We identified 380 genes at 129 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold (p < 2.36E-6). Of them, 29 genes were located in 11 novel regions that were at least 1Mb away from published GWAS hits. The rest of TWAS-significant genes were located in 118 known genomic loci from previous GWAS of breast cancer. After conditioning on previous GWAS index variants, we found that 22 genes located in known GWAS loci remained statistically significant. Our study maps potential target genes in more than half of known GWAS loci and discovers multiple new loci, providing new insights into breast cancer genetics.

The authors have declared no competing interest.

This work was supported by the National Cancer Institute (R01-CA242929, R01-CA228198), Breast Cancer Research Foundation (BCRF-21-071), and the NIDDK (P30 DK20595). For BCAC data, the breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Minist&eacutere de l'&Egraveconomie, de la Science et de l'Innovation du Qu&eacutebec' through Genome Qu&eacutebec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al (Nature, 2017). This research has been conducted using the UK Biobank Resource under the Application Number 49564. The authors thank the participants, investigators, and staff of the UK Biobank for providing them with the resources to pursue this research.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

BCAC summary statistics, https://bcac.ccge.medschl.cam.ac.uk/bcacdata/oncoarray/oncoarray-and-combined-summary-result; UK Biobank, http://ukbiobank.ac.uk;

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