Article

Nature 447, 1087-1093 (28 June 2007) | doi:10.1038/nature05887; Received 9 February 2007; Accepted 30 April 2007; Published online 27 May 2007; Corrected 28 June 2007

Genome-wide association study identifies novel breast cancer susceptibility loci

Douglas F. Easton1, Karen A. Pooley2, Alison M. Dunning2, Paul D. P. Pharoah2, Deborah Thompson1, Dennis G. Ballinger3, Jeffery P. Struewing4, Jonathan Morrison2, Helen Field2, Robert Luben5, Nicholas Wareham5, Shahana Ahmed2, Catherine S. Healey2, Richard Bowman6The SEARCH collaborators and , Kerstin B. Meyer7, Christopher A. Haiman8, Laurence K. Kolonel9, Brian E. Henderson8, Loic Le Marchand9, Paul Brennan10, Suleeporn Sangrajrang11, Valerie Gaborieau10, Fabrice Odefrey10, Chen-Yang Shen12, Pei-Ei Wu12, Hui-Chun Wang12, Diana Eccles13, D. Gareth Evans14, Julian Peto15, Olivia Fletcher16, Nichola Johnson16, Sheila Seal17, Michael R. Stratton17,18, Nazneen Rahman17, Georgia Chenevix-Trench19, Stig E. Bojesen20, Børge G. Nordestgaard20, Christen K. Axelsson21, Montserrat Garcia-Closas22, Louise Brinton22, Stephen Chanock23, Jolanta Lissowska24, Beata Peplonska25, Heli Nevanlinna26, Rainer Fagerholm26, Hannaleena Eerola26,27, Daehee Kang28, Keun-Young Yoo28,29, Dong-Young Noh28, Sei-Hyun Ahn30, David J. Hunter31,32, Susan E. Hankinson32, David G. Cox31, Per Hall33, Sara Wedren33, Jianjun Liu34, Yen-Ling Low34, Natalia Bogdanova35,36, Peter Schürmann36, Thilo Dörk36, Rob A. E. M. Tollenaar37, Catharina E. Jacobi38, Peter Devilee39, Jan G. M. Klijn40, Alice J. Sigurdson41, Michele M. Doody41, Bruce H. Alexander42, Jinghui Zhang4, Angela Cox43, Ian W. Brock43, Gordon MacPherson43, Malcolm W. R. Reed44, Fergus J. Couch45, Ellen L. Goode45, Janet E. Olson45, Hanne Meijers-Heijboer46,47, Ans van den Ouweland47, André Uitterlinden48, Fernando Rivadeneira48, Roger L. Milne49, Gloria Ribas49, Anna Gonzalez-Neira49, Javier Benitez49, John L. Hopper50, Margaret McCredie51, Melissa Southey50, Graham G. Giles52, Chris Schroen53, Christina Justenhoven54, Hiltrud Brauch54, Ute Hamann55, Yon-Dschun Ko56, Amanda B. Spurdle19, Jonathan Beesley19, Xiaoqing Chen19kConFab and AOCS Management Group and , Arto Mannermaa118,119, Veli-Matti Kosma118,119, Vesa Kataja118,120, Jaana Hartikainen118,119, Nicholas E. Day65, David R. Cox63 & Bruce A. J. Ponder62,67

  1. CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care and,
  2. Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
  3. Perlegen Sciences, Inc., 2021 Stierlin Court, Mountain View, California 94043, USA.
  4. Laboratory of Population Genetics, US National Cancer Institute, Bethesda, Maryland 20892, USA.
  5. EPIC, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
  6. MRC Dunn Clinical Nutrition Centre, Cambridge CB2 0XY, UK.
  7. Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, UK.
  8. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
  9. Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813, USA.
  10. International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon 69008, France.
  11. National Cancer Institute, Bangkok 10400, Thailand.
  12. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
  13. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
  14. Regional Genetic Service, St Mary's Hospital, Manchester M13 0JH, UK.
  15. London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK, and Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
  16. Breakthrough Breast Cancer Research Centre, London SW3 6JB, UK.
  17. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
  18. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  19. Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
  20. Departments of Clinical Biochemistry and
  21. Breast Surgery, Herlev and Bispebjerg University Hospitals, University of Copenhagen, DK-2730 Herlev, Denmark.
  22. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA.
  23. Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA.
  24. Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw 02781, Poland.
  25. Nofer Institute of Occupational Medicine, Lodz 90950, Poland.
  26. Departments of Obstetrics and Gynecology, and
  27. Department of Oncology, Helsinki University Central Hospital, Helsinki 00029, Finland.
  28. Seoul National University College of Medicine, Seoul 151-742, Korea.
  29. National Cancer Center, Goyang 411-769, Korea.
  30. Ulsan University College of Medicine, Ulsan 680-749, Korea.
  31. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, Massachusetts 02115, USA.
  32. Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave., Boston, Massachusetts 02115, USA.
  33. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE-171 77, Sweden.
  34. Population Genetics, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Republic of Singapore.
  35. Department of Radiation Oncology and
  36. Department of Gynecology and Obstetrics, Hannover Medical School, D-30625 Hannover, Germany.
  37. Department of Surgery and
  38. Department of Medical Decision Making and
  39. Departments of Human Genetics and Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
  40. Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands.
  41. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
  42. Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
  43. Institute for Cancer Studies and
  44. Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield S10 2RX, UK.
  45. Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
  46. VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
  47. Department of Clinical Genetics and
  48. Internal Medicine, Erasmus University, Rotterdam NL-3015-GE, the Netherlands.
  49. Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.
  50. Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Carlton, Victoria 3053, Australia.
  51. Department of Preventive and Social Medicine, University of Otago, Dunedin 9001, New Zealand.
  52. Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria 3053, Australia.
  53. Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.
  54. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharamcology, 70376 Stuttgart and University of Tuebingen, 72074 Tuebingen, Germany.
  55. Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany.
  56. Evangelische Kliniken Bonn gGmbH Johanniter Krankenhaus, 53113 Bonn, Germany.
  57. Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
  58. Insitute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio, Kuopio FIN-70210, Finland.
  59. Departments of Oncology and Pathology, University Hospital of Kuopio, Kuopio FIN-70211, Finland.
  60. Department of Oncology, Vaasa Central Hospital, Vaasa 65130, Finland.
  61. Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
  62. Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
  63. Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Victoria 3050, Australia.
  64. Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
  65. Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
  66. Anatomical Pathology, Royal Women's Hospital, Carlton, Victoria 3053, Australia.
  67. Molecular Genetics Laboratory, Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
  68. Departments of Translational and Medical Oncology, Westmead Hospital, Westmead, New South Wales 2145, Australia.
  69. Cancer Biology Laboratory, TVW Institute for Child Health Research, Subiaco, Western Australia 6008, Australia.
  70. Pathology Centre, Queen Elizabeth Medical Centre, Nedlands, Western Australia 6009, Australia.
  71. Silverton Place, 101 Wickham Terrace, Brisbane, Queensland 4000, Australia.
  72. Department of Public Health and Community Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.
  73. John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, Australian Capital Territory 2601, Australia.
  74. NSW Breast Cancer Institute, PO Box 143, Westmead, New South Wales 2145, Australia.
  75. Department of Biochemistry, University of Queensland, St. Lucia, Queensland 4072, USA.
  76. Molecular and Cytogenetics Unit, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
  77. Royal Hobart Hospital, GPO Box 1061L, Hobart, Tasmania 7001, Australia.
  78. Medical Psychology Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales 2204, Australia.
  79. Australian Genome Research Facility, Walter & Eliza Hall Medical Research Institute, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
  80. Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide/Hanson Institute, PO Box 14, Rundle Mall, South Australia 5000, Australia.
  81. Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
  82. Queensland Institute of Medical Research, Herston, Queensland 4006, Australia.
  83. Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital ,Westmead, New South Wales 2145, Australia.
  84. Department of Clinical Genetics, Liverpool Health Service, PO Box 103, Liverpool, New South Wales 2170, Australia.
  85. Mutation Research Centre, St Vincent's Hospital, Victoria Parade, Fitzroy, Victoria 3065, Australia.
  86. Centre for Genetic Epidemiology, The University of Melbourne, Level 2 723 Swanston Street, Carlton, Victoria 3053, Australia.
  87. Molecular and Clinical Genetics, Level 1 Building 65, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
  88. Department of Pathology, University of Queensland Medical School, Herston, New South Wales 4006, Australia.
  89. Central Regional Genetic Services, Wellington Hospital, Private bag 7902, Wellington South 6039, New Zealand.
  90. Molecular Department of Pathology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
  91. Hunter Genetics, Hunter Area Health Service, Waratah, New South Wales 2310, Australia.
  92. Clinical Chemistry, Princess Margret Hospital for Children, Box D184, Perth, Western Australia 6001, Australia.
  93. Department of Multicultural Health, University of Sydney, New South Wales 2052, Australia.
  94. Tissue Pathology, Institute of Medical & Veterinary Science, Adelaide, South Australia 5000, Australia.
  95. Family Cancer Clinic, Monash Medical Centre, Clayton, Victoria 3168, Australia.
  96. Faculty of Medicine, Royal North Shore Hospital, Vindin House, St Leonards, New South Wales 2065, Australia.
  97. Department of Haematology, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.
  98. Eskitis Institute of Cell & Molecular Therapies, School of Biomolecular and Biomedical Sciences, Griffith University, Nathan, Queensland 4111, Australia.
  99. Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, Waratah, New South Wales 2298, Australia.
  100. Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
  101. Victorian Clinical Genetics Service, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia.
  102. Queensland Clinical Genetic Service, Royal Children's Hospital, Bramston Terrace, Herston, Queensland 4020, Australia.
  103. Clinical Biochemistry Unit, Canterbury Health Labs, PO Box 151, Christchurch 8140, New Zealand.
  104. Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne Street, Carlton, Victoria 3053, Australia.
  105. Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
  106. Genetic Services of WA, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Western Australia 6008, Australia.
  107. Wollongong Hereditary Cancer Clinic, Wollongong Public Hospital, Private Mail Bag 8808, South Coast Mail Centre, New South Wales 2521, Australia.
  108. Department of Medical Genetics, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
  109. Familial Cancer Clinic, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
  110. Breast and Ovarian Cancer Genetics, Monash Medical Centre, 871 Centre Road, Bentleigh East, Victoria 3165, Australia.
  111. Centre for Molecular Environmental, Genetic & Analytic Epidemiology, University of Melbourne, Melbourne, Victoria 3010, Australia.
  112. School of Population Health, The University of Melbourne, 723 Swanston Street, Carlton, Victoria 3053, Australia.
  113. Medical Oncology, Westmead Hospital, Westmead, New South Wales 2145, Australia.
  114. Familial Cancer Service, Department of Medicine, Westmead Hospital, Westmead, New South Wales 2145, Australia.
  115. Breast Endocrine and Surgical Unit, Royal Adelaide Hospital, North Terrace, South Australia 5000, Australia.
  116. Molecular Pathology Department, Southern Cross Pathology, Monash Medical Centre, Clayton, Victoria 3168, Australia.
  117. Molecular and Cellular Pathology, The University of Queensland, Herston, Queensland 4006, Australia.
  118. Department of Psychological Medicine, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
  119. Breast Cancer Laboratory, Walter and Eliza Hall Institute, PO Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
  120. Medical Oncology and Clinical Haematology Unit, Western Hospital, Footscray, Victoria 3011, Australia.
  121. WA Centre for Cancer, Edith Cowan University, Churchlands, Western Australia 6018, Australia.
  122. Department of Psychological Medicine, University of Sydney, New South Wales 2006, Australia.
  123. Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
  124. Cancer Epidemiology Research Unit, NSW Cancer Council, 153 Dowling Street, Woolloomooloo, New South Wales 2011, Australia.
  125. Department of Oncology, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
  126. School of Public Health, Queensland University of Technology, Victoria Park, Kelvin Grove, Queensland 4059, Australia.
  127. St Vincent's Breast Clinic, PO Box 4751, Toowoomba, Queensland 4350, Australia.
  128. Radiation Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
  129. Genetic Services, Auckland Hospital, Private Bag 92024, Auckland 1142, New Zealand.
  130. Cancer Genetics Laboratory, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
  131. Department of Cytogenetics and Molecular Genetics, Women and Children's Hospital, Adelaide, South Australia 5006, Australia.
  132. Hancock Family Breast Cancer Foundation, PO Locked Bag 2, West Perth, Western Australia 6005, Australia.
  133. Oncology Service, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand.
  134. Molecular Pathology Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia.
  135. Section of Cytology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales 2145, Australia.
  136. School of Surgery and Pathology, QE11 Medical Centre, M block 2nd Floor, Nedlands, Western Australia 6907, Australia.
  137. South View Clinic, Suite 13, Level 3 South Street, Kogarah, New South Wales 2217, Australia.
  138. Department of Obstetrics and Gynaecology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  139. Department of Radiology, Royal Perth Hospital, Box X2213, Perth 6011, Western Australia, Australia.
  140. Murdoch Institute, Royal Children's Hospital, Parkville, Victoria 3050, Australia.
  141. Molecular Genetics of Cancer Division, Walter & Eliza Hall Medical Research Institute, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
  142. Department of Medical Oncology, St Vincents Hospital, Darlinghurst, New South Wales 2010, Australia.
  143. Cabrini Hospital, 183 Wattletree Road, Malvern, Victoria 3144, Australia.
  144. Family Cancer Clinic, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
  145. Medical Psychology Research Unit, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
  146. Cancer Genomics & Biochemistry Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia.
  147. Obstetrics & Gynaecology, Westmead Hospital, University of Sydney, New South Wales 2006, Australia.
  148. Lists of consortia participants and affiliations appear after author affiliations.

Correspondence to: Douglas F. Easton1 Correspondence and requests for materials should be addressed to D.F.E. (Email: d.easton@srl.cam.ac.uk).

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Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

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