A Transcriptome-wide Association Study of 229,000 Women Identifies New Candidate Susceptibility Genes for Breast Cancer

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, 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.

Citing Articles

A Multi-omic study integrating plasma protein, multiple tissues, and single-cell identifies RNASET2 as a key gene for lung cancer.

Shi J, Zhang L Discov Oncol. 2025; 16(1):152.

PMID: 39930075 PMC: 11811349. DOI: 10.1007/s12672-025-01899-4.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Jia G, Chen Z, Ping J, Cai Q, Tao R, Li C Nat Genet. 2025; 57(1):80-87.

PMID: 39753771 DOI: 10.1038/s41588-024-02031-y.

Leveraging genome-wide association studies to better understand the etiology of cancers.

Sonehara K, Okada Y Cancer Sci. 2024; 116(2):288-296.

PMID: 39561785 PMC: 11786324. DOI: 10.1111/cas.16402.

Enhancing disease risk gene discovery by integrating transcription factor-linked trans-variants into transcriptome-wide association analyses.

He J, Perera D, Wen W, Ping J, Li Q, Lyu L Nucleic Acids Res. 2024; 53(1).

PMID: 39535029 PMC: 11724290. DOI: 10.1093/nar/gkae1035.

A proteome-wide association study identifies putative causal proteins for breast cancer risk.

Zhao T, Xu S, Ping J, Jia G, Dou Y, Henry J Br J Cancer. 2024; 131(11):1796-1804.

PMID: 39468330 PMC: 11589835. DOI: 10.1038/s41416-024-02879-1.

References

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

Turcot V, Lu Y, Highland H, Schurmann C, Justice A, Fine R . Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2017; 50(1):26-41. PMC: 5945951. DOI: 10.1038/s41588-017-0011-x. View

Kim M, Lee S, Koo J, Jung K, Park I, Jeong J . Anaplastic lymphoma kinase gene copy number gain in inflammatory breast cancer (IBC): prevalence, clinicopathologic features and prognostic implication. PLoS One. 2015; 10(3):e0120320. PMC: 4372579. DOI: 10.1371/journal.pone.0120320. View

Kamangar F, Dores G, Anderson W . Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006; 24(14):2137-50. DOI: 10.1200/JCO.2005.05.2308. View

. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489(7414):57-74. PMC: 3439153. DOI: 10.1038/nature11247. View

Stegle O, Parts L, Piipari M, Winn J, Durbin R . Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nat Protoc. 2012; 7(3):500-7. PMC: 3398141. DOI: 10.1038/nprot.2011.457. View

Finucane H, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P . Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015; 47(11):1228-35. PMC: 4626285. DOI: 10.1038/ng.3404. View

Lee D, Gorkin D, Baker M, Strober B, Asoni A, McCallion A . A method to predict the impact of regulatory variants from DNA sequence. Nat Genet. 2015; 47(8):955-61. PMC: 4520745. DOI: 10.1038/ng.3331. View

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

10.

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

11.

Garcia-Closas M, Couch F, Lindstrom S, Michailidou K, Schmidt M, Brook M . Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013; 45(4):392-8, 398e1-2. PMC: 3771695. DOI: 10.1038/ng.2561. View

12.

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx B . Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016; 48(3):245-52. PMC: 4767558. DOI: 10.1038/ng.3506. View

13.

Marouli E, Graff M, Medina-Gomez C, Lo K, Wood A, Kjaer T . Rare and low-frequency coding variants alter human adult height. Nature. 2017; 542(7640):186-190. PMC: 5302847. DOI: 10.1038/nature21039. View

14.

DeLuca D, Levin J, Sivachenko A, Fennell T, Nazaire M, Williams C . RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics. 2012; 28(11):1530-2. PMC: 3356847. DOI: 10.1093/bioinformatics/bts196. View

15.

Milne R, Kuchenbaecker K, Michailidou K, Beesley J, Kar S, Lindstrom S . Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet. 2017; 49(12):1767-1778. PMC: 5808456. DOI: 10.1038/ng.3785. View

16.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

17.

Li Y, Peart M, Prives C . Stxbp4 regulates DeltaNp63 stability by suppression of RACK1-dependent degradation. Mol Cell Biol. 2009; 29(14):3953-63. PMC: 2704755. DOI: 10.1128/MCB.00449-09. View

18.

Southey M, Goldgar D, Winqvist R, Pylkas K, Couch F, Tischkowitz M . PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet. 2016; 53(12):800-811. PMC: 5200636. DOI: 10.1136/jmedgenet-2016-103839. View

19.

Barbeira A, Dickinson S, Bonazzola R, Zheng J, Wheeler H, Torres J . Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat Commun. 2018; 9(1):1825. PMC: 5940825. DOI: 10.1038/s41467-018-03621-1. View

20.

Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne R . Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013; 45(4):353-61, 361e1-2. PMC: 3771688. DOI: 10.1038/ng.2563. View