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

Guochong Jia¹, Zhishan Chen¹, Jie Ping¹, Qiuyin Cai¹, Ran Tao², Chao Li¹, Joshua A Bauer³, Yuhan Xie⁴, Stefan Ambs⁵, Mollie E Barnard⁶, Yu Chen⁷, Ji-Yeob Choi^{8

9}, Yu-Tang Gao¹⁰, Montserrat Garcia-Closas¹¹, Jian Gu¹², Jennifer J Hu¹³, Motoki Iwasaki¹⁴, Esther M John¹⁵, Sun-Seog Kweon^{16

17}, Christopher I Li¹⁸, Koichi Matsuda¹⁹, Keitaro Matsuo^{20

21}, Katherine L Nathanson^{22

23}, Barbara Nemesure²⁴, Olufunmilayo I Olopade²⁵, Tuya Pal²⁶, Sue K Park^{9

27

28}, Boyoung Park²⁹, Michael F Press³⁰, Maureen Sanderson³¹, Dale P Sandler³², Chen-Yang Shen^{33

34}, Melissa A Troester³⁵, Song Yao³⁶, Ying Zheng³⁷, Thomas Ahearn¹¹, Abenaa M Brewster³⁸, Adeyinka Falusi³⁹, Anselm J M Hennis^{24

40}, Hidemi Ito^{41

42}, Michiaki Kubo⁴³, Eun-Sook Lee^{44

45}, Timothy Makumbi⁴⁶, Paul Ndom⁴⁷, Dong-Young Noh^{48

49}, Katie M O'Brien³², Oladosu Ojengbede⁵⁰, Andrew F Olshan³⁵, Min-Ho Park⁵¹, Sonya Reid⁵², Taiki Yamaji¹⁴, Gary Zirpoli⁶, Ebonee N Butler³⁵, Maosheng Huang¹², Siew-Kee Low⁴³, John Obafunwa⁵³, Clarice R Weinberg⁵⁴, Haoyu Zhang¹¹, Hongyu Zhao⁴, Michelle L Cote^{55

56}, Christine B Ambrosone³⁶, Dezheng Huo⁵⁷, Bingshan Li⁵⁸, Daehee Kang^{8

9}, Julie R Palmer⁶, Xiao-Ou Shu¹, Christopher A Haiman⁵⁹, Xingyi Guo¹, Jirong Long¹, Wei Zheng⁶⁰

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
⁵ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁷ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁸ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
⁹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰ State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹² Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Public Health Sciences, University of Miami School of Medicine, Miami, FL, USA.
¹⁴ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁵ Department of Epidemiology and Population Health and Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, South Korea.
¹⁷ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
¹⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁹ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
²⁰ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
²¹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²² Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁴ Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁵ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, USA.
²⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
²⁸ Cancer Research Institute, Seoul National University, Seoul, South Korea.
²⁹ Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, South Korea.
³⁰ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
³¹ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
³² Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
³³ College of Public Health, China Medical University, Taichong, Taiwan.
³⁴ Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³⁵ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁶ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
³⁷ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³⁸ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³⁹ Genetic and Bioethics Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁴⁰ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
⁴¹ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁴² Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴³ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴⁴ National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea.
⁴⁵ Hospital, National Cancer Center, Goyang, South Korea.
⁴⁶ Department of Surgery, Mulago Hospital, Kampala, Uganda.
⁴⁷ Yaounde General Hospital, Yaounde, Cameroon.
⁴⁸ College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁴⁹ Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
⁵⁰ Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁵¹ Department of Surgery, Chonnam National University Medical School, Gwangju, South Korea.
⁵² Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵³ Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Lagos, Nigeria.
⁵⁴ Biostatistics and Computational Biology Branch, National Institutes of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁵⁵ Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
⁵⁶ Simon Comprehensive Cancer Center, Indianapolis, IN, USA.
⁵⁷ Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
⁵⁸ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
⁵⁹ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁶⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.

PMID: 39753771
PMCID: PMC12184877 (available on 2026-01-03)
DOI: 10.1038/s41588-024-02031-y

Observational Study

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

Guochong Jia et al. Nat Genet. 2025 Jan.

. 2025 Jan;57(1):80-87.

doi: 10.1038/s41588-024-02031-y. Epub 2025 Jan 3.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
⁵ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁷ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁸ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
⁹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰ State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹² Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Public Health Sciences, University of Miami School of Medicine, Miami, FL, USA.
¹⁴ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁵ Department of Epidemiology and Population Health and Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, South Korea.
¹⁷ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
¹⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁹ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
²⁰ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
²¹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²² Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁴ Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁵ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, USA.
²⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
²⁸ Cancer Research Institute, Seoul National University, Seoul, South Korea.
²⁹ Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, South Korea.
³⁰ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
³¹ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
³² Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
³³ College of Public Health, China Medical University, Taichong, Taiwan.
³⁴ Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³⁵ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁶ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
³⁷ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³⁸ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³⁹ Genetic and Bioethics Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁴⁰ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
⁴¹ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁴² Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴³ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴⁴ National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea.
⁴⁵ Hospital, National Cancer Center, Goyang, South Korea.
⁴⁶ Department of Surgery, Mulago Hospital, Kampala, Uganda.
⁴⁷ Yaounde General Hospital, Yaounde, Cameroon.
⁴⁸ College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁴⁹ Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
⁵⁰ Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁵¹ Department of Surgery, Chonnam National University Medical School, Gwangju, South Korea.
⁵² Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵³ Department of Pathology and Forensic Medicine, Lagos State University Teaching Hospital, Lagos, Nigeria.
⁵⁴ Biostatistics and Computational Biology Branch, National Institutes of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁵⁵ Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
⁵⁶ Simon Comprehensive Cancer Center, Indianapolis, IN, USA.
⁵⁷ Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
⁵⁸ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
⁵⁹ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁶⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.

PMID: 39753771
PMCID: PMC12184877 (available on 2026-01-03)
DOI: 10.1038/s41588-024-02031-y

Abstract

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses.

PubMed Disclaimer

Conflict of interest statement

Competing interests: O.I.O is co-founder at CancerIQ, serves as Scientific Advisor at Tempus and is on the Board of 54gene. The other authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Methods-only references

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous