Letter | Published:

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Nature Genetics volume 47, pages 373380 (2015) | Download Citation

Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10−8. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

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Acknowledgements

The authors thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out.

BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.

Author information

Affiliations

  1. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Kyriaki Michailidou
    • , Joe Dennis
    • , Michael J Lush
    • , Manjeet K Bolla
    • , Qin Wang
    • , Paul P D P Pharoah
    •  & Douglas F Easton
  2. Department of Genetics, QIMR (Queensland Institute for Medical Research) Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Jonathan Beesley
    •  & Georgia Chenevix-Trench
  3. Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Sara Lindstrom
    • , David J Hunter
    •  & Peter Kraft
  4. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

    • Sander Canisius
  5. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Mel J Maranian
    • , Mitul Shah
    • , Barbara J Perkins
    • , Craig Luccarini
    • , Caroline Baynes
    • , Shahana Ahmed
    • , Catherine S Healey
    • , Paul P D P Pharoah
    • , Alison M Dunning
    •  & Douglas F Easton
  6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Kamila Czene
    • , Mikael Eriksson
    • , Hatef Darabi
    • , Judith S Brand
    • , Jingmei Li
    • , Keith Humphreys
    •  & Per Hall
  7. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Stig E Bojesen
    • , Børge G Nordestgaard
    •  & Sune F Nielsen
  8. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Stig E Bojesen
    • , Børge G Nordestgaard
    •  & Sune F Nielsen
  9. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Stig E Bojesen
    •  & Børge G Nordestgaard
  10. Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Henrik Flyger
  11. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

    • Nazneen Rahman
    • , Clare Turnbull
    • , Minouk J Schoemaker
    • , Anthony J Swerdlow
    •  & Montserrat Garcia-Closas
  12. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

    • Olivia Fletcher
    • , Alan Ashworth
    • , Nick Orr
    •  & Montserrat Garcia-Closas
  13. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

    • Julian Peto
    • , Lorna Gibson
    •  & Isabel dos-Santos-Silva
  14. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jenny Chang-Claude
    • , Anja Rudolph
    • , Ursula Eilber
    •  & Sabine Behrens
  15. Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

    • Dieter Flesch-Janys
  16. Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

    • Dieter Flesch-Janys
  17. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Heli Nevanlinna
    • , Taru A Muranen
    • , Sofia Khan
    •  & Kirsimari Aaltonen
  18. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.

    • Kristiina Aittomäki
  19. Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Carl Blomqvist
  20. Center for Cancer Epidemiology and Prevention, University of Chicago, Chicago, Illinois, USA.

    • Habibul Ahsan
    •  & Muhammad G Kibriya
  21. Department of Health Studies, University of Chicago, Chicago, Illinois, USA.

    • Habibul Ahsan
    •  & Muhammad G Kibriya
  22. Department of Medicine, University of Chicago, Chicago, Illinois, USA.

    • Habibul Ahsan
  23. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.

    • Habibul Ahsan
  24. Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA.

    • Habibul Ahsan
  25. Department of Health Research and Policy–Epidemiology, Stanford University School of Medicine, Stanford, California, USA.

    • Alice S Whittemore
    •  & Esther M John
  26. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.

    • Alice S Whittemore
    •  & Esther M John
  27. Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA.

    • Esther M John
  28. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Kathleen E Malone
  29. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Marilie D Gammon
  30. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA.

    • Regina M Santella
  31. Cancer Registry of Norway, Oslo, Norway.

    • Giske Ursin
  32. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, Melbourne, Victoria, Australia.

    • Enes Makalic
    •  & Daniel F Schmidt
  33. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Graham Casey
    • , Christopher A Haiman
    • , Fredrick Schumacher
    • , Brian E Henderson
    • , Anna H Wu
    • , Chiu-chen Tseng
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    •  & Daniel O Stram
  34. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • Susan M Gapstur
    • , Mia M Gaudet
    •  & W Ryan Diver
  35. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Loic Le Marchand
  36. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland, USA.

    • Christine D Berg
  37. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

    • Stephen J Chanock
    • , Jonine Figueroa
    • , Robert N Hoover
    •  & Louise Brinton
  38. Vesalius Research Center, VIB, Leuven, Belgium.

    • Diether Lambrechts
  39. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  40. Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium.

    • Patrick Neven
    • , Hans Wildiers
    •  & Erik van Limbergen
  41. Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

    • Marjanka K Schmidt
    • , Annegien Broeks
    • , Senno Verhoef
    •  & Sten Cornelissen
  42. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Fergus J Couch
  43. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Janet E Olson
    • , Emily Hallberg
    • , Celine Vachon
    •  & Susan Slager
  44. Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Amsterdam, the Netherlands.

    • Quinten Waisfisz
    • , Hanne Meijers-Heijboer
    •  & Muriel A Adank
  45. Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Rob B van der Luijt
  46. Human Genetics Division, Genome Institute of Singapore, Singapore.

    • Jianjun Liu
  47. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

    • Daehee Kang
    •  & Sue K Park
  48. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.

    • Daehee Kang
    • , Ji-Yeob Choi
    •  & Sue K Park
  49. Cancer Research Institute, Seoul National University, Seoul, Korea.

    • Daehee Kang
    • , Ji-Yeob Choi
    •  & Sue K Park
  50. Seoul National University College of Medicine, Seoul, Korea.

    • Keun-Young Yoo
  51. Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.

    • Keitaro Matsuo
  52. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Hidemi Ito
  53. Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

    • Hiroji Iwata
  54. Epidemiology Center for Disease Control and Prevention, Mie University Hospital, Tsu, Japan.

    • Kazuo Tajima
  55. INSERM), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France.

    • Pascal Guénel
    • , Thérèse Truong
    •  & Marie Sanchez
  56. University Paris–Sud, UMRS 1018, Villejuif, France.

    • Pascal Guénel
    • , Thérèse Truong
    •  & Marie Sanchez
  57. Université Paris Sorbonne Cité, UMRS 775, INSERM, Paris, France.

    • Claire Mulot
  58. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.

    • Barbara Burwinkel
    • , Frederik Marme
    • , Harald Surowy
    • , Christof Sohn
    •  & Rongxi Yang
  59. Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Barbara Burwinkel
    • , Harald Surowy
    •  & Rongxi Yang
  60. National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.

    • Frederik Marme
  61. Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Anna González-Neira
    • , Javier Benitez
    • , Guillermo Pita
    • , M Rosario Alonso
    • , Nuria Álvarez
    •  & Daniel Herrero
  62. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.

    • Javier Benitez
  63. Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.

    • M Pilar Zamora
  64. Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.

    • Jose Ignacio Arias Perez
  65. Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Xiao-Ou Shu
    • , Hui Cai
    • , William Blot
    • , Qiuyin Cai
    • , Wei Zheng
    • , Sandra L Halverson
    • , Martha Shrubsole
    •  & Jirong Long
  66. Shanghai Center for Disease Control and Prevention, Changning, China.

    • Wei Lu
  67. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
  68. Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.

    • Angela Cox
    •  & Malcolm W R Reed
  69. Department of Oncology, University of Sheffield, Sheffield, UK.

    • Angela Cox
    •  & Malcolm W R Reed
  70. Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.

    • Simon S Cross
  71. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Irene L Andrulis
    •  & Gord Glendon
  72. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Irene L Andrulis
  73. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Julia A Knight
  74. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Julia A Knight
  75. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
  76. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
  77. Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.

    • Elinor J Sawyer
  78. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Ian Tomlinson
  79. Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

    • Ian Tomlinson
  80. Department of Surgery, School of Medicine, National University of Ireland, Galway, Ireland.

    • Michael J Kerin
    •  & Nicola Miller
  81. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

    • Annika Lindblom
  82. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

    • Sara Margolin
  83. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.

    • Soo Hwang Teo
  84. Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia.

    • Soo Hwang Teo
    • , Cheng Har Yip
    • , Nur Aishah Mohd Taib
    •  & Gie-Hooi Tan
  85. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

    • Maartje J Hooning
    • , Antoinette Hollestelle
    •  & John W M Martens
  86. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • J Margriet Collée
  87. International Epidemiology Institute, Rockville, Maryland, USA.

    • William Blot
  88. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Lisa B Signorello
    •  & Dimitrios Trichopoulos
  89. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • John L Hopper
    • , Carmel Apicella
    • , Graham G Giles
    •  & Roger L Milne
  90. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

    • Melissa C Southey
    •  & Helen Tsimiklis
  91. Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Chen-Yang Shen
    •  & Pei-Ei Wu
  92. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Chen-Yang Shen
    • , Chia-Ni Hsiung
    •  & Pei-Ei Wu
  93. School of Public Health, China Medical University, Taichung, Taiwan.

    • Chen-Yang Shen
  94. Cancer Center, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.

    • Ming-Feng Hou
  95. Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.

    • Ming-Feng Hou
  96. Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.

    • Vessela N Kristensen
    • , Silje Nord
    •  & Grethe I Grenaker Alnaes
  97. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Vessela N Kristensen
  98. Department of Clinical Molecular Biology (EpiGen), University of Oslo, Oslo, Norway.

    • Vessela N Kristensen
  99. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Graham G Giles
    •  & Roger L Milne
  100. Department of Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia.

    • Catriona McLean
  101. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Federico Canzian
  102. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.

    • Dimitrios Trichopoulos
  103. Hellenic Health Foundation, Athens, Greece.

    • Dimitrios Trichopoulos
  104. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands.

    • Petra Peeters
  105. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Petra Peeters
    •  & Marc J Gunter
  106. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Arctic University of Norway, Tromsø, Norway.

    • Eiliv Lund
  107. Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden.

    • Malin Sund
  108. School of Clinical Medicine, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  109. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Istituto per lo Studio e la Prevenzione Oncologica (ISPO), Florence, Italy.

    • Domenico Palli
  110. Section for Epidemiology, Aarhus University, Aarhus, Denmark.

    • Lotte Maxild Mortensen
  111. INSERM Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France.

    • Laure Dossus
  112. Université Paris–Sud, Villejuif, France.

    • Laure Dossus
  113. Department of Epidemiology, Consejería de Sanidad y Política Social, CIBER de Epidemiología y Salud Pública, Murcia, Spain.

    • Jose-Maria Huerta
  114. Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.

    • Alfons Meindl
  115. Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Cologne, Germany.

    • Rita K Schmutzler
  116. Center for Integrated Oncology (CIO), University Hospital Cologne, Cologne, Germany.

    • Rita K Schmutzler
  117. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Cologne, Germany.

    • Rita K Schmutzler
  118. Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.

    • Christian Sutter
  119. Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.

    • Kenneth Muir
    • , Artitaya Lophatananon
    •  & Sarah Stewart-Brown
  120. Institute of Population Health, University of Manchester, Manchester, UK.

    • Kenneth Muir
  121. Ministry of Public Health, Nonthaburi, Thailand.

    • Pornthep Siriwanarangsan
  122. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.

    • Mikael Hartman
  123. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

    • Mikael Hartman
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    •  & Kee Seng Chia
  124. Division of General Surgery, National University Health System, Singapore.

    • Ching Wan Chan
  125. Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center of the Erlangen-Nuremberg Metropolitan Region, Erlangen, Germany.

    • Peter A Fasching
    • , Alexander Hein
    • , Matthias W Beckmann
    •  & Lothar Haeberle
  126. Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  127. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hermann Brenner
    • , Aida Karina Dieffenbach
    •  & Volker Arndt
  128. German Cancer Consortium (DKTK), Heidelberg, Germany.

    • Hermann Brenner
    • , Aida Karina Dieffenbach
    •  & Hiltrud Brauch
  129. Saarland Cancer Registry, Saarbrücken, Germany.

    • Christa Stegmaier
  130. Division of Breast Cancer Research, Institute of Cancer Research, London, UK.

    • Anthony J Swerdlow
  131. Department of Medicine, McGill University, Montreal, Quebec, Canada.

    • Mark S Goldberg
  132. Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada.

    • Mark S Goldberg
  133. Département de Santé Environnementale et Santé au Travail, Ecole de Santé Publique, Université de Montréal, Montreal, Quebec, Canada.

    • France Labrèche
  134. Département de Médecine Sociale et Préventive, Ecole de Santé Publique, Université de Montréal, Montreal, Quebec, Canada.

    • France Labrèche
  135. Centre Hospitalier Universitaire de Québec Research Center, Quebec City, Quebec, Canada.

    • Martine Dumont
    •  & Jacques Simard
  136. Department of Molecular Medicine, Laval University, Quebec City, Quebec, Canada.

    • Martine Dumont
    •  & Jacques Simard
  137. Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu/Oulu University Hospital, Oulu, Finland.

    • Robert Winqvist
    •  & Katri Pylkäs
  138. Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.

    • Arja Jukkola-Vuorinen
  139. Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.

    • Mervi Grip
  140. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Hiltrud Brauch
  141. University of Tübingen, Tübingen, Germany.

    • Hiltrud Brauch
  142. German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hiltrud Brauch
  143. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Ute Hamann
    • , Maria Kabisch
    •  & Diana Torres
  144. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.

    • Thomas Brüning
  145. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.

    • Paolo Radice
  146. Fondazione Istituto FIRC (Italian Foundation for Cancer Research) di Oncologia Molecolare (IFOM), Milan, Italy.

    • Paolo Peterlongo
  147. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.

    • Siranoush Manoukian
  148. Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.

    • Loris Bernard
  149. Cogentech Cancer Genetic Test Laboratory, Milan, Italy.

    • Loris Bernard
  150. Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

    • Natalia V Bogdanova
  151. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

    • Thilo Dörk
  152. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.

    • Arto Mannermaa
    • , Veli-Matti Kosma
    •  & Jaana M Hartikainen
  153. Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.

    • Arto Mannermaa
    • , Veli-Matti Kosma
    •  & Jaana M Hartikainen
  154. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.

    • Arto Mannermaa
    • , Veli-Matti Kosma
    •  & Jaana M Hartikainen
  155. Cancer Center, Kuopio University Hospital, Kuopio, Finland.

    • Vesa Kataja
  156. Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland.

    • Vesa Kataja
  157. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
  158. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
  159. Department of Surgical Oncology, Leiden University Medical Center, Leiden, the Netherlands.

    • Robert A E M Tollenaar
  160. Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

    • Caroline Seynaeve
  161. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Christi J Van Asperen
  162. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

    • Anna Jakubowska
    • , Jan Lubinski
    • , Katarzyna Jaworska
    •  & Tomasz Huzarski
  163. National Cancer Institute of Thailand, Bangkok, Thailand.

    • Suleeporn Sangrajrang
  164. International Agency for Research on Cancer, Lyon, France.

    • Valerie Gaborieau
    • , Paul Brennan
    •  & James McKay
  165. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.

    • Amanda E Toland
  166. Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Christine B Ambrosone
  167. Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products (IRRP), National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece.

    • Drakoulis Yannoukakos
  168. Institute of Human Genetics, Pontificia Universidad Javeriana, Bogotá, Colombia.

    • Diana Torres
  169. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.

    • Susan L Neuhausen
  170. Department of Epidemiology, University of California–Irvine, Irvine, California, USA.

    • Hoda Anton-Culver
  171. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.

    • Daniel C Tessier
    • , Daniel Vincent
    •  & Francois Bacot

Consortia

  1. BOCS

    A full list of members and affiliations appears in the Supplementary Note.

  2. kConFab Investigators

    A full list of members and affiliations appears in the Supplementary Note.

  3. AOCS Group

    A full list of members and affiliations appears in the Supplementary Note.

  4. NBCS

    A full list of members and affiliations appears in the Supplementary Note.

  5. GENICA Network

    A full list of members and affiliations appears in the Supplementary Note.

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Contributions

K. Michailidou and D.F.E. performed the statistical analysis and drafted the manuscript. D.F.E. conceived and coordinated the synthesis of the iCOGS array and led the BCAC. P.H. coordinated COGS. J. Benitez led the iCOGS genotyping working group. A.G.-N., G.P., M.R.A., N.Á., D.H., J. Benitez, D.V., F.B., D.C.T., J.S., A.M.D., C.L., C. Baynes, S.A., C.S.H. and M.J.M. coordinated genotyping of the iCOGS array. M.G.-C., P.P.D.P.P. and M.K.S. led the BCAC pathology and survival working group. J.C.-C. led the BCAC risk factor working group. A.M.D. and G.C.-T. led the iCOGS quality control working group. J. Beesley, J.D. and M.J.L. provided bioinformatics support. M.K.B. and Q. Wang provided data management support for BCAC. S. Canisius provided analysis of the TCGA expression data. J.L.H., M.C.S., H.T. and C.A. coordinated ABCFS. M.K.S., A.B., S.V. and S. Cornelissen coordinated ABCS. K. Muir, A. Lophatananon, S.S.-B. and P.S. coordinated ACP. P.A.F., A. Hein, M.W.B. and L.H. coordinated BBCC. J.P., I.d.-S.-S., O.F. and L.G. coordinated BBCS. E.J.S., I.T., M.J.K. and N.M. coordinated BIGGS. P.K., D.J.H., S.L., S.M.G., M.M.G., W.R.D., C.A.H., F.S., B.E.H., L.L.M., C.D.B., S.J.C., J.F. and R.N.H. coordinated BPC3. B.B., F.M., H.S. and C. Sohn coordinated BSUCH. N.R. and C. Turnbull coordinated BOCS. P.G., T.T., C. Mulot and M. Sanchez coordinated CECILE. S.E.B., B.G.N., H.F. and S.F.N. coordinated CGPS. A.G.-N., J. Benitez, M.P.Z. and J.I.A.P. coordinated CNIO-BCS. H.A.-C. and S.L.N. coordinated CTS. H. Brenner, A.K.D., V.A. and C. Stegmaier coordinated ESTHER. A. Meindl, R.K.S., C. Sutter and R.Y. coordinated GC-HBOC. H. Brauch, U.H. and T.B. coordinated GENICA. H.N., T.A.M., K. Aittomäki, C. Blomqvist, K. Aaltonen and S.K. coordinated HEBCS. K. Matsuo, H. Ito, H. Iwata and K.T. coordinated HERPACC. T.D. and N.V.B. coordinated HMBCS. A. Lindblom and S. Margolin coordinated KARBAC. A. Mannermaa, V.K., V.-M.K. and J.M.H. coordinated KBCP. G.C.-T. and J. Beesley coordinated kConFab/AOCS. A.H.W., C. Tseng, D.V.D.B. and D.O.S. coordinated LAABC. D.L., P.N., H.W. and E.v.L. coordinated LMBC. J.C.-C., D.F.-J., U.E., S.B. and A.R. coordinated MARIE. P.R., P. Peterlongo, S. Manoukian and L. Bernard coordinated MBCSG. F.J.C., J.E.O., E.H. and C.V. coordinated MCBCS. G.G.G., R.L.M. and C. McLean coordinated MCCS. C.A.H., B.E.H., F.S. and L.L.M. coordinated MEC. J.S., M.S.G., F.L. and M.D. coordinated MTLGEBCS. S.H.T., C.H.Y., N.A.M.T. and G.-H.T. coordinated MYBRCA. V.N.K., G.I.G.A. and S.N. coordinated NBCS. W.Z., S.L.H., M. Shrubsole and J. Long coordinated NBHS. R.W., K.P., A.J.-V. and M.G. coordinated OBCS. I.L.A., J.A.K., G.G. and A.M.M. coordinated OFBCR. P.D., R.A.E.M.T., C. Seynaeve and C.J.V.A. coordinated ORIGO. M.G.-C., J.F., S.J.C. and L. Brinton coordinated PBCS. K.C., H.D., M.E. and J.S.B. coordinated pKARMA. M.J.H., A. Hollestelle, J.W.M.M. and J.M.C. coordinated RBCS. P.H., J. Li, J. Liu and K.H. coordinated SASBAC. X.-O.S., W.L., Y.-T.G. and H.C. coordinated SBCGS. A.C., S.S.C. and M.W.R.R. coordinated SBCS. W.B., L.B.S. and Q.C. coordinated SCCS. M. Shah and B.J.P. coordinated SEARCH. D.K., J.-Y.C., S.K.P. and K.-Y.Y. coordinated SEBCS. M.H., H.M., K.S.C. and C.W.C. coordinated SGBCC. U.H., M.K. and D. Torres coordinated SKKDKFZS. A.J., J. Lubinski, K.J. and T.H. coordinated SZBCS. S. Sangrajrang, V.G., P.B. and J.M. coordinated TBCS. F.J.C., S. Slager, A.E.T., C.B.A. and D.Y. coordinated the TNBCC. C.-Y.S., C.-N.H., P.-E.W. and M.-F.H. coordinated TWBCS. A.J.S.,A.A., N.O. and M.J.S. coordinated UKBGS. H.A., M.G.K., A.S.W., E.M.J., K.E.M., M.D.G., R.M.S., G.U., E.M., D.F.S. and G.C. coordinated EBCG GWAS. Q. Waisfisz, H.M.-H., M.A.A. and R.B.v.d.L. coordinated DFBBCS GWAS. D.F.E., N.R. and C. Turnbull coordinated UK2 GWAS. F.C., D. Trichopoulos, P. Peeters, E.L., M. Sund, K.-T.K., M.J.G., D.P., L.D., J.-M.H. and L.M.M. coordinated EPIC. All authors provided critical review of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Douglas F Easton.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1–9 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 10

    Set of all 522 SNPs correlated with 1 of the 15 lead SNPs and that could not be ruled out as potentially causal (based on a likelihood ratio of 100:1).

  2. 2.

    Supplementary Table 11

    Associations between the 15 new susceptibility variants and expression of neighboring genes in breast tumors and normal breast tissue, from the TCGA data set.

About this article

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DOI

https://doi.org/10.1038/ng.3242

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