Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Babatunde Adedokun¹, Zhaohui Du², Guimin Gao³, Thomas U Ahearn⁴, Kathryn L Lunetta⁵, Gary Zirpoli⁶, Jonine Figueroa⁷, Esther M John⁸, Leslie Bernstein⁹, Wei Zheng¹⁰, Jennifer J Hu¹¹, Regina G Ziegler⁴, Sarah Nyante¹², Elisa V Bandera¹³, Sue A Ingles², Michael F Press¹⁴, Sandra L Deming-Halverson¹⁰, Jorge L Rodriguez-Gil¹⁵, Song Yao¹⁶, Temidayo O Ogundiran¹⁷, Oladosu Ojengbede¹⁸, William Blot¹⁰, Melissa A Troester¹⁹, Katherine L Nathanson²⁰, Anselm Hennis^{21

22}, Barbara Nemesure²², Stefan Ambs²³, Peter N Fiorica³, Lara E Sucheston-Campbell²⁴, Jeannette T Bensen¹⁹, Lawrence H Kushi²⁵, Gabriela Torres-Mejia²⁶, Donglei Hu²⁷, Laura Fejerman²⁷, Manjeet K Bolla²⁸, Joe Dennis²⁸, Alison M Dunning²⁹, Douglas F Easton^{28

29}, Kyriaki Michailidou³⁰, Paul D P Pharoah^{28

29}, Qin Wang²⁸, Dale P Sandler³¹, Jack A Taylor³¹, Katie M O'Brien³¹, Cari M Kitahara³², Adeyinka G Falusi³³, Chinedum Babalola³⁴, Joel Yarney³⁵, Baffour Awuah³⁶, Beatrice Addai-Wiafe³⁷; GBHS Study Team; Stephen J Chanock⁴, Andrew F Olshan¹⁹, Christine B Ambrosone¹⁶, David V Conti², Elad Ziv²⁷, Olufunmilayo I Olopade¹, Montserrat Garcia-Closas⁴, Julie R Palmer⁶, Christopher A Haiman³⁸, Dezheng Huo^{39

40}

Affiliations

¹ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, IL, USA.
² Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁶ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁷ Usher Institute and CRUK Edinburgh Centre, University of Edinburgh, Edinburgh, UK.
⁸ Departments of Epidemiology & Population Health and of Medicine (Oncology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Biomarkers of Early Detection and Prevention, Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
¹¹ Department of Public Health Sciences, University of Miami, Miami, FL, USA.
¹² Department of Radiology, University of North Carolina, Chapel Hill, NC, USA.
¹³ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁴ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁵ Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
¹⁶ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹⁷ Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁸ Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
²⁰ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ University of the West Indies, Bridgetown, Barbados.
²² Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²³ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA.
²⁴ Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
²⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
²⁶ Center for Population Health Research, Instituto Nacional de Salud Publica, Cuernavaca, Mexico.
²⁷ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁰ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
³¹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
³² Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
³³ Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria.
³⁴ Department of Pharmaceutical Chemistry, University of Ibadan, Ibadan, Oyo, Nigeria.
³⁵ Korle Bu Teaching Hospital, Accra, Ghana.
³⁶ Komfo Anokye Teaching Hospital, Kumasi, Ghana.
³⁷ Peace and Love Hospital, Kumasi, Ghana.
³⁸ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. haiman@usc.edu.
³⁹ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, IL, USA. dhuo@health.bsd.uchicago.edu.
⁴⁰ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. dhuo@health.bsd.uchicago.edu.

PMID: 34234117
PMCID: PMC8263739
DOI: 10.1038/s41467-021-24327-x

Meta-Analysis

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Babatunde Adedokun et al. Nat Commun. 2021.

. 2021 Jul 7;12(1):4198.

doi: 10.1038/s41467-021-24327-x.

Authors

Affiliations

¹ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, IL, USA.
² Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁶ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁷ Usher Institute and CRUK Edinburgh Centre, University of Edinburgh, Edinburgh, UK.
⁸ Departments of Epidemiology & Population Health and of Medicine (Oncology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Biomarkers of Early Detection and Prevention, Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
¹¹ Department of Public Health Sciences, University of Miami, Miami, FL, USA.
¹² Department of Radiology, University of North Carolina, Chapel Hill, NC, USA.
¹³ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁴ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁵ Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
¹⁶ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹⁷ Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁸ Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
¹⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
²⁰ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ University of the West Indies, Bridgetown, Barbados.
²² Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²³ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA.
²⁴ Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
²⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
²⁶ Center for Population Health Research, Instituto Nacional de Salud Publica, Cuernavaca, Mexico.
²⁷ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
²⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³⁰ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
³¹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
³² Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
³³ Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria.
³⁴ Department of Pharmaceutical Chemistry, University of Ibadan, Ibadan, Oyo, Nigeria.
³⁵ Korle Bu Teaching Hospital, Accra, Ghana.
³⁶ Komfo Anokye Teaching Hospital, Kumasi, Ghana.
³⁷ Peace and Love Hospital, Kumasi, Ghana.
³⁸ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. haiman@usc.edu.
³⁹ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, IL, USA. dhuo@health.bsd.uchicago.edu.
⁴⁰ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. dhuo@health.bsd.uchicago.edu.

PMID: 34234117
PMCID: PMC8263739
DOI: 10.1038/s41467-021-24327-x

Abstract

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

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Conflict of interest statement

The authors declare no competing interests.

References

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Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Affiliations

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical