Multi-ancestry transcriptome-wide association studies uncover insights into breast cancer genetics and biology

Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet their target genes remain largely unknown. We conduct multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We develop ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation using genomic and transcriptomic data from 652 normal female tissue samples and apply these models to GWAS data of 178,534 cases and 248,300 controls for association analyses. We identify 290 genes associated with breast cancer risk, including 103 previously unreported and 46 not located at known GWAS loci, and 39 genes show distinct associations with breast cancer risk by estrogen-receptor status. Single-cell RNA sequencing and in vitro experiment data provide additional functional evidence for 169 genes. These genes are enriched in pathways implicated in breast carcinogenesis. Our study uncovers insights into breast cancer genetics and biology.

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Journal
Nature Communications
Published
2026-05-30
DOI
https://doi.org/10.1038/s41467-026-73801-x
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Multi-ancestry transcriptome-wide association studies uncover insights into breast cancer genetics and biology

Maureen Sanderson, Siew‐Kee Low, Guochong Jia, B Nemesure et al.
Nature Communications
Genetic Associations and Epidemiology
article

Multi-ancestry transcriptome-wide association studies uncover insights into breast cancer genetics and biology

Maureen Sanderson, Siew‐Kee Low, Guochong Jia, B Nemesure, Michael F. Press, Mollie E. Barnard, Jennifer J. Hu, Joshua A. Bauer, Michiaki Kubo, Eun-Sook Lee, Min‐Ho Park, Michelle L. Cote, Maosheng Huang, Clarice Ring Weinberg, Berthe SE Mapoko, Gary Zirpoli, Sun-Seog Kweon, Dezheng Huo, Tuya Pal, Melissa A. Troester, Xingyi Guo, Keitaro MATSUO, Ebonee N. Butler, Esther M. John, Sue K. Park, Yu-Tang Gao, Timothy Makumbi, Yuhan Xie, Montserrat Garcia-Closas, Motoki Iwasaki, Andrew F. Olshan, Haoyu Zhang, Hongyu Zhao, Christine B. Ambrosone, Boyoung Park, Dong-Young Noh, Xiao-Ou Shu, Anselm J. M. Hennis, Julie R. Palmer, Ran Tao, Katie M. O’Brien, John Obafunwa, Thomas Ahearn, Daehee Kang, Jian Gu, Koichi Matsuda, Katherine L. Nathanson, Abenaa M. Brewster, Olufunmilayo I. Olopade, Dale P. Sandler, Jifeng Wang, Christopher A. Haiman, Wei Zheng, Oladosu Ojengbede, Hidemi ITO, Ji-Yeob Choi, Yu Chen, Jie Ping, Ying Zheng, Stefan Ambs, Qiuyin Cai, Sonya Reid, Jirong Long, Bingshan Li, Christopher I. Li, Taiki Yamaji, Adeyinka Falusi, Song Yao
article en

Abstract

Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet their target genes remain largely unknown. We conduct multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We develop ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation using genomic and transcriptomic data from 652 normal female tissue samples and apply these models to GWAS data of 178,534 cases and 248,300 controls for association analyses. We identify 290 genes associated with breast cancer risk, including 103 previously unreported and 46 not located at known GWAS loci, and 39 genes show distinct associations with breast cancer risk by estrogen-receptor status. Single-cell RNA sequencing and in vitro experiment data provide additional functional evidence for 169 genes. These genes are enriched in pathways implicated in breast carcinogenesis. Our study uncovers insights into breast cancer genetics and biology.

Nature Communications
Boston University (US), Chonnam National University (KR), University of North Carolina at Chapel Hill (US), University of Southern California (US), Meharry Medical College (US), Indiana University Health (US), Roswell Park Comprehensive Cancer Center (US), National Institutes of Health (US), The University of Texas MD Anderson Cancer Center (US), Seoul National University (KR), University of Miami (US), Chicago Department of Public Health (US), University of Ibadan (NG), Shanghai Jiao Tong University (CN), Vanderbilt University (US), Keck Hospital of USC (US), Renji Hospital (CN), Mulago Hospital (UG), Seoul National University Hospital (KR), Yale University (US), University of Chicago (US), Stony Brook School (US), Fred Hutch Cancer Center (US), Central Hospital of Yaoundé (CM), National Institute of Environmental Health Sciences (US), Indiana Cancer Consortium (US), Shanghai Cancer Institute (CN), Lagos State University Teaching Hospital (NG), National Cancer Center (KR), Aichi Cancer Center (JP), State Key Laboratory of Oncogene and Related Genes (CN), National Cancer Institute (US), Chonnam National University Hwasun Hospital (KR), RIKEN Center for Integrative Medical Sciences (JP), University of the West Indies (BB), Shanghai Municipal Center For Disease Control Prevention (CN), Division of Cancer Epidemiology and Genetics, Hanyang University (KR), Indiana University – Purdue University Indianapolis (US), New York University (US), Stony Brook University (US), Nagoya University (JP), The University of Tokyo (JP), University of Pennsylvania (US), Vanderbilt University Medical Center (US), Stanford University (US)
National Institutes of Health
Good health and well-being
Openalex Percentile: Top 5%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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