Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

Guochong Jia¹, Jie Ping¹, Xiang Shu², Yaohua Yang¹, Qiuyin Cai¹, Sun-Seog Kweon³, Ji-Yeob Choi⁴, Michiaki Kubo⁵, Sue K Park⁴, Manjeet K Bolla⁶, Joe Dennis⁶, Qin Wang⁶, Xingyi Guo¹, Bingshan Li⁷, Ran Tao⁸, Kristan J Aronson⁹, Tsun L Chan¹⁰, Yu-Tang Gao¹¹, Mikael Hartman¹², Weang Kee Ho¹³, Hidemi Ito¹⁴, Motoki Iwasaki¹⁵, Hiroji Iwata¹⁶, Esther M John¹⁷, Yoshio Kasuga¹⁸, Mi-Kyung Kim¹⁹, Allison W Kurian²⁰, Ava Kwong²¹, Jingmei Li²², Artitaya Lophatananon²³, Siew-Kee Low⁵, Shivaani Mariapun²⁴, Koichi Matsuda²⁵, Keitaro Matsuo²⁶, Kenneth Muir²³, Dong-Young Noh²⁷, Boyoung Park²⁸, Min-Ho Park²⁹, Chen-Yang Shen³⁰, Min-Ho Shin³¹, John J Spinelli³², Atsushi Takahashi³³, Chiuchen Tseng³⁴, Shoichiro Tsugane³⁵, Anna H Wu³⁴, Taiki Yamaji¹⁵, Ying Zheng³⁶, Alison M Dunning³⁷, Paul D P Pharoah³⁸, Soo-Hwang Teo³⁹, Daehee Kang⁴⁰, Douglas F Easton³⁸, Jacques Simard⁴¹, Xiao-Ou Shu¹, Jirong Long¹, Wei Zheng⁴²

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, USA.
² Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
⁴ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
⁵ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
⁸ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Public Health Sciences and Queen's Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁰ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China.
¹¹ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹² Department of Surgery, National University Hospital, Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹³ Department of Applied Mathematics, Faculty of Engineering, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia.
¹⁴ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁵ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁶ Department of Breast Oncology, Aichi Cancer Center, Nagoya, Aichi, Japan.
¹⁷ Departments of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA; Departments of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Surgery, Nagano Matsushiro General Hospital, Nagano, Japan.
¹⁹ Division of Cancer Epidemiology and Management, National Cancer Center, Goyang, Korea.
²⁰ Departments of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA, USA.
²¹ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR, China; Department of Surgery, University of Hong Kong, Hong Kong SAR, China; Department of Surgery, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China.
²² Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Human Genetics, Genome Institute of Singapore, Singapore, Singapore; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²³ Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK; Institute of Population Health, University of Manchester, Manchester, UK.
²⁴ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
²⁵ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
²⁶ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁷ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
²⁸ Department of Medicine, Hanyang University College of Medicine, Seoul, Korea.
²⁹ Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
³⁰ College of Public Health, China Medical University, Taichong, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³¹ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.
³² Department of Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
³³ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
³⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁵ National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan.
³⁶ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³⁷ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁹ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia; Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpar, Malaysia.
⁴⁰ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Korea.
⁴¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval, Research Center, Québec City, QC, Canada.
⁴² Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, USA. Electronic address: wei.zheng@vanderbilt.edu.

PMID: 36356581
PMCID: PMC9748250
DOI: 10.1016/j.ajhg.2022.10.011

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

Guochong Jia et al. Am J Hum Genet. 2022.

. 2022 Dec 1;109(12):2185-2195.

doi: 10.1016/j.ajhg.2022.10.011. Epub 2022 Nov 9.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, USA.
² Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
⁴ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
⁵ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
⁸ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Public Health Sciences and Queen's Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁰ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China.
¹¹ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹² Department of Surgery, National University Hospital, Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹³ Department of Applied Mathematics, Faculty of Engineering, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia.
¹⁴ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁵ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁶ Department of Breast Oncology, Aichi Cancer Center, Nagoya, Aichi, Japan.
¹⁷ Departments of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA; Departments of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Surgery, Nagano Matsushiro General Hospital, Nagano, Japan.
¹⁹ Division of Cancer Epidemiology and Management, National Cancer Center, Goyang, Korea.
²⁰ Departments of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA, USA.
²¹ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong SAR, China; Department of Surgery, University of Hong Kong, Hong Kong SAR, China; Department of Surgery, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China.
²² Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Human Genetics, Genome Institute of Singapore, Singapore, Singapore; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²³ Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK; Institute of Population Health, University of Manchester, Manchester, UK.
²⁴ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
²⁵ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
²⁶ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁷ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
²⁸ Department of Medicine, Hanyang University College of Medicine, Seoul, Korea.
²⁹ Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
³⁰ College of Public Health, China Medical University, Taichong, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³¹ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.
³² Department of Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
³³ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
³⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁵ National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan.
³⁶ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³⁷ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁹ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia; Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpar, Malaysia.
⁴⁰ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Korea.
⁴¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval, Research Center, Québec City, QC, Canada.
⁴² Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, USA. Electronic address: wei.zheng@vanderbilt.edu.

PMID: 36356581
PMCID: PMC9748250
DOI: 10.1016/j.ajhg.2022.10.011

Abstract

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10^-8 and a Bonferroni-corrected p < 4.6 × 10^-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Keywords: breast cancer; multi-ancestry meta-analysis; transcriptome-wide association study.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

**Figure 1**
Comparison of risk estimates for lead risk variants between Asian- and European-ancestry women The red regression line shows the trend of risk estimates in both ancestry groups. To be conservative, the regression was performed excluding four variants with risk estimates >0.15 in European-ancestry women, which could be outliers or with a high leverage. The black dashed diagonal line shows where risk estimates are the same in both ancestries.

See this image and copyright information in PMC

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Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

Affiliations

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical