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Genome-wide association study identifies novel breast cancer susceptibility loci

Nature 447, 1087–1093 (28 June 2007) | Download Citation

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Abstract

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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Change history

  • 28 June 2007

    In the AOP version of this Article, Kristy Driver was omitted from The SEARCH collaborators. This and the Supplementary Information acknowledgements have now been corrected for both print and online publication on 28 June 2007.

References

  1. 1.

    Familial breast cancer: Collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. Lancet 358, 1389–1399 (2001)

  2. 2.

    et al. A strong candidate for the breast and ovarian-cancer susceptibility gene BRCA1. Science 266, 66–71 (1994)

  3. 3.

    et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995)

  4. 4.

    et al. Average risks of breast and ovarian cancer associated with mutations in BRCA1 or BRCA2 detected in case series unselected for family history: A combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003)

  5. 5.

    et al. A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosom. Cancer 45, 646–655 (2006)

  6. 6.

    et al. Polygenic susceptibility to breast cancer and implications for prevention. Nature Genet. 31, 33–36 (2002)

  7. 7.

    , , & The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br. J. Cancer 91, 1580–1590 (2004)

  8. 8.

    et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39, 165–167 (2007)

  9. 9.

    et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl Cancer Inst. 97, 813–822 (2005)

  10. 10.

    et al. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet. 31, 55–59 (2002)

  11. 11.

    et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007)

  12. 12.

    et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature Genet. 38, 873–875 (2006)

  13. 13.

    et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genet. 38, 1239–1241 (2006)

  14. 14.

    CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from ten studies. Am. J. Hum. Genet. 74, 1175–1182 (2004)

  15. 15.

    et al. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics 39, 352–358 (2007); corrigendum. 39, 688 (2007)

  16. 16.

    How many more breast cancer predisposition genes are there? Breast Cancer Res. 1, 1–4 (1999)

  17. 17.

    & Variation is the spice of life. Nature Genet. 27, 234–236 (2001)

  18. 18.

    et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005)

  19. 19.

    , , , & Two-stage designs for gene-disease association studies. Biometrics 58, 163–170 (2002)

  20. 20.

    & Polygenic inheritance of breast cancer: Implications for design of association studies. Genet. Epidemiol. 25, 190–202 (2003)

  21. 21.

    et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

  22. 22.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999)

  23. 23.

    , & Recent developments in genomewide association scans: A workshop summary and review. Am. J. Hum. Genet. 77, 337–345 (2005)

  24. 24.

    et al. A common variant associated with prostate cancer in European and African populations. Nature Genet. 38, 652–658 (2006)

  25. 25.

    et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nature Genet. 39, 645–649 (2007)

  26. 26.

    et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nature Genet. 39, 631–637 (2007)

  27. 27.

    et al. PReMod: a database of genome-wide mammalian cis-regulatory module predictions. Nucleic Acids Res. 35, D122–D126 (2007)

  28. 28.

    , & Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Mol. Cancer Res. 2, 643–652 (2004)

  29. 29.

    et al. Bek and Flg, 2 receptors to members of the Fgf family, are amplified in subsets of human breast cancers. Oncogene 6, 659–663 (1991)

  30. 30.

    , & Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 61, 3541–3543 (2001)

  31. 31.

    et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007)

  32. 32.

    et al. Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum. Mol. Genet. 14, 2349–2356 (2005)

  33. 33.

    et al. EPIC-Norfolk: Study design and characteristics of the cohort. Br. J. Cancer 80, 95–103 (1999)

  34. 34.

    Breast Cancer Association Consortium. Commonly studied SNPs and breast cancer: Negative results from 12,000 – 32,000 cases and controls from the Breast Cancer Association Consortium. J. Natl Cancer Inst. 98, 1382–1396 (2006)

  35. 35.

    et al. The Ensembl genome database project. Nucleic Acids Res. 30, 38–41 (2002)

  36. 36.

    et al. Comprehensive human genome amplification using multiple displacement amplification. Proc. Natl Acad. Sci. USA 99, 5261–5266 (2002)

  37. 37.

    et al. Efficiency and power in genetic association studies. Nature Genet. 37, 1217–1223 (2005)

  38. 38.

    , & The admixture maximum likelihood test: A novel experiment-wise test of association between disease and multiple SNPs. Genet. Epidemiol. 30, 636–643 (2006)

  39. 39.

    , , , & Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet. 70, 425–434 (2002)

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Acknowledgements

The authors thank the women who took part in this research, and all the funders and support staff who made this study possible. The principal funding for this study was provided by Cancer Research UK. Detailed acknowledgements are provided in Supplementary Information.

Author Contributions D.F.E., A.M.D., P.D.P.P., D.R.C. and B.A.J.P. designed the study and obtained financial support. D.G.B. and D.R.C. directed the genotyping of stages 1 and 2. D.F.E. and D.T. conducted the statistical analysis. K.A.P. and A.M.D. coordinated the genotyping for stage 3 and the fine-scale mapping of the FGFR2 and TNRC9 loci. J.P.S. and J.Z. performed resequencing and analysis of the FGFR2 locus. K.A.P., S.A., C.S.H., R.B., C.A.H., L.K.K., B.E.H., L.L.M., P.B., S.S., V.G., F.O., C-Y. S., P-E.W. and H-C.W. conducted genotyping for the fine-scale mapping. R.L., J.M., H.F. and K.B.M. provided bioinformatics support. D.E., D.G.E., J.P., O.F., N.J., S.S., M.R.S. and N.R. coordinated the studies used in stage 1. N.W. and N.E.D. coordinated the EPIC study used in stages 1 and 2. The remaining authors coordinated the studies in stage 3 and undertook genotyping in those studies. D.F.E. drafted the manuscript, with substantial contributions from K.A.P., A.M.D., P.D.P.P. and B.A.J.P. All authors contributed to the final paper.

Author information

Affiliations

  1. CR‐UK Genetic Epidemiology Unit, Department of Public Health and Primary Care and,

    • Douglas F. Easton
    •  & Deborah Thompson

  2. Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.

    • Karen A. Pooley
    • , Alison M. Dunning
    • , Paul D. P. Pharoah
    • , Jonathan Morrison
    • , Helen Field
    • , Shahana Ahmed
    •  & Catherine S. Healey

  3. Perlegen Sciences, Inc., 2021 Stierlin Court, Mountain View, California 94043, USA.

    • Dennis G. Ballinger

  4. Laboratory of Population Genetics, US National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Jeffery P. Struewing
    •  & Jinghui Zhang

  5. EPIC, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.

    • Robert Luben
    •  & Nicholas Wareham

  6. MRC Dunn Clinical Nutrition Centre, Cambridge CB2 0XY, UK.

    • Richard Bowman

  7. Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, UK.

    • Kerstin B. Meyer

  8. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Christopher A. Haiman
    •  & Brian E. Henderson

  9. Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813, USA.

    • Laurence K. Kolonel
    •  & Loic Le Marchand

  10. International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon 69008, France.

    • Paul Brennan
    • , Valerie Gaborieau
    •  & Fabrice Odefrey

  11. National Cancer Institute, Bangkok 10400, Thailand.

    • Suleeporn Sangrajrang

  12. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.

    • Chen-Yang Shen
    • , Pei-Ei Wu
    •  & Hui-Chun Wang

  13. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.

    • Diana Eccles

  14. Regional Genetic Service, St Mary’s Hospital, Manchester M13 0JH, UK.

    • D. Gareth Evans

  15. London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK, and Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

    • Julian Peto

  16. Breakthrough Breast Cancer Research Centre, London SW3 6JB, UK.

    • Olivia Fletcher
    •  & Nichola Johnson

  17. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

    • Sheila Seal
    • , Michael R. Stratton
    •  & Nazneen Rahman

  18. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Michael R. Stratton

  19. Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.

    • Georgia Chenevix-Trench
    • , Amanda B. Spurdle
    • , Jonathan Beesley
    •  & Xiaoqing Chen

  20. Departments of Clinical Biochemistry and

    • Stig E. Bojesen
    •  & Børge G. Nordestgaard

  21. Breast Surgery, Herlev and Bispebjerg University Hospitals, University of Copenhagen, DK‐2730 Herlev, Denmark.

    • Christen K. Axelsson

  22. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA.

    • Montserrat Garcia-Closas
    •  & Louise Brinton

  23. Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA.

    • Stephen Chanock

  24. Cancer Center and M. Sklodowska‐Curie Institute of Oncology, Warsaw 02781, Poland.

    • Jolanta Lissowska

  25. Nofer Institute of Occupational Medicine, Lodz 90950, Poland.

    • Beata Peplonska

  26. Departments of Obstetrics and Gynecology, and

    • Heli Nevanlinna
    • , Rainer Fagerholm
    •  & Hannaleena Eerola

  27. Department of Oncology, Helsinki University Central Hospital, Helsinki 00029, Finland.

    • Hannaleena Eerola

  28. Seoul National University College of Medicine, Seoul 151‐742, Korea.

    • Daehee Kang
    • , Keun-Young Yoo
    •  & Dong-Young Noh

  29. National Cancer Center, Goyang 411‐769, Korea.

    • Keun-Young Yoo

  30. Ulsan University College of Medicine, Ulsan 680‐749, Korea.

    • Sei-Hyun Ahn

  31. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, Massachusetts 02115, USA.

    • David J. Hunter
    •  & David G. Cox

  32. Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Ave., Boston, Massachusetts 02115, USA.

    • David J. Hunter
    •  & Susan E. Hankinson

  33. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE‐171 77, Sweden.

    • Per Hall
    •  & Sara Wedren

  34. Population Genetics, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Republic of Singapore.

    • Jianjun Liu
    •  & Yen-Ling Low

  35. Department of Radiation Oncology and

    • Natalia Bogdanova

  36. Department of Gynecology and Obstetrics, Hannover Medical School, D‐30625 Hannover, Germany.

    • Natalia Bogdanova
    • , Peter Schürmann
    •  & Thilo Dörk

  37. Department of Surgery and

    • Rob A. E. M. Tollenaar

  38. Department of Medical Decision Making and

    • Catharina E. Jacobi

  39. Departments of Human Genetics and Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.

    • Peter Devilee

  40. Family Cancer Clinic, Department of Medical Oncology, Erasmus MC‐Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands.

    • Jan G. M. Klijn

  41. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Alice J. Sigurdson
    •  & Michele M. Doody

  42. Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.

    • Bruce H. Alexander

  43. Institute for Cancer Studies and

    • Angela Cox
    • , Ian W. Brock
    •  & Gordon MacPherson

  44. Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield S10 2RX, UK.

    • Malcolm W. R. Reed

  45. Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

    • Fergus J. Couch
    • , Ellen L. Goode
    •  & Janet E. Olson

  46. VU University Medical Center, 1007 MB Amsterdam, the Netherlands.

    • Hanne Meijers-Heijboer

  47. Department of Clinical Genetics and

    • Hanne Meijers-Heijboer
    •  & Ans van den Ouweland

  48. Internal Medicine, Erasmus University, Rotterdam NL‐3015‐GE, the Netherlands.

    • André Uitterlinden
    •  & Fernando Rivadeneira

  49. Spanish National Cancer Centre (CNIO), Madrid E‐28029, Spain.

    • Roger L. Milne
    • , Gloria Ribas
    • , Anna Gonzalez-Neira
    •  & Javier Benitez

  50. Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Carlton, Victoria 3053, Australia.

    • John L. Hopper
    •  & Melissa Southey

  51. Department of Preventive and Social Medicine, University of Otago, Dunedin 9001, New Zealand.

    • Margaret McCredie

  52. Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Victoria 3053, Australia.

    • Graham G. Giles

  53. Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.

    • Chris Schroen

  54. Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharamcology, 70376 Stuttgart and University of Tuebingen, 72074 Tuebingen, Germany.

    • Christina Justenhoven
    •  & Hiltrud Brauch

  55. Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany.

    • Ute Hamann

  56. Evangelische Kliniken Bonn gGmbH Johanniter Krankenhaus, 53113 Bonn, Germany.

    • Yon-Dschun Ko

  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.

    • Craig Luccarini
    • , Don Conroy
    • , Mitul Shah
    • , Hannah Munday
    • , Clare Jordan
    • , Barbara Perkins
    • , Judy West
    • , Karen Redman
    •  & Kristy Driver

  62. Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

    • Morteza Aghmesheh
    •  & Bruce A. J. Ponder

  63. Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, Victoria 3050, Australia.

    • David Amor
    •  & David R. Cox

  64. Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

    • Lesley Andrews
    • , Barbara Bennett
    • , Bettina Meiser
    • , Kathy Tucker
    •  & Janet Tyler

  65. Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.

    • Yoland Antill
    • , Sarah-Jane Dawson
    • , Kelly Phillips
    • , Clare Scott
    •  & Nicholas E. Day

  66. Anatomical Pathology, Royal Women’s Hospital, Carlton, Victoria 3053, Australia.

    • Jane Armes

  67. Molecular Genetics Laboratory, Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia.

    • Shane Armitage
    • , Leanne Arnold
    • , Alison Jones
    •  & Bruce A. J. Ponder

  68. Departments of Translational and Medical Oncology, Westmead Hospital, Westmead, New South Wales 2145, Australia.

    • Rosemary Balleine

  69. Cancer Biology Laboratory, TVW Institute for Child Health Research, Subiaco, Western Australia 6008, Australia.

    • Glenn Begley

  70. Pathology Centre, Queen Elizabeth Medical Centre, Nedlands, Western Australia 6009, Australia.

    • John Beilby

  71. Silverton Place, 101 Wickham Terrace, Brisbane, Queensland 4000, Australia.

    • Ian Bennett

  72. Department of Public Health and Community Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.

    • Geoffrey Berry

  73. John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, Australian Capital Territory 2601, Australia.

    • Anneke Blackburn

  74. NSW Breast Cancer Institute, PO Box 143, Westmead, New South Wales 2145, Australia.

    • Meagan Brennan

  75. Department of Biochemistry, University of Queensland, St. Lucia, Queensland 4072, USA.

    • Melissa Brown

  76. Molecular and Cytogenetics Unit, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

    • Michael Buckley

  77. Royal Hobart Hospital, GPO Box 1061L, Hobart, Tasmania 7001, Australia.

    • Jo Burke
    •  & Evelyn Humphrey

  78. Medical Psychology Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales 2204, Australia.

    • Phyllis Butow

  79. Australian Genome Research Facility, Walter & Eliza Hall Medical Research Institute, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

    • Keith Byron

  80. Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide/Hanson Institute, PO Box 14, Rundle Mall, South Australia 5000, Australia.

    • David Callen

  81. Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia.

    • Ian Campbell
    • , Joe Sambrook
    •  & Heather Thorne

  82. Queensland Institute of Medical Research, Herston, Queensland 4006, Australia.

    • Georgia Chenevix-Trench
    • , Nick Hayward
    • , Amanda Spurdle
    • , Adele Green
    •  & Penny Webb

  83. Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital ,Westmead, New South Wales 2145, Australia.

    • Christine Clarke
    •  & Graham Mann

  84. Department of Clinical Genetics, Liverpool Health Service, PO Box 103, Liverpool, New South Wales 2170, Australia.

    • Alison Colley

  85. Mutation Research Centre, St Vincent’s Hospital, Victoria Parade, Fitzroy, Victoria 3065, Australia.

    • Dick Cotton

  86. Centre for Genetic Epidemiology, The University of Melbourne, Level 2 723 Swanston Street, Carlton, Victoria 3053, Australia.

    • Jisheng Cui
    • , Roger Milne
    •  & Melissa Southey

  87. Molecular and Clinical Genetics, Level 1 Building 65, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.

    • Bronwyn Culling

  88. Department of Pathology, University of Queensland Medical School, Herston, New South Wales 4006, Australia.

    • Margaret Cummings

  89. Central Regional Genetic Services, Wellington Hospital, Private bag 7902, Wellington South 6039, New Zealand.

    • Joanne Dixon

  90. Molecular Department of Pathology, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia.

    • Alexander Dobrovic
    •  & Paul Waring

  91. Hunter Genetics, Hunter Area Health Service, Waratah, New South Wales 2310, Australia.

    • Tracy Dudding
    •  & Rodney Scott

  92. Clinical Chemistry, Princess Margret Hospital for Children, Box D184, Perth, Western Australia 6001, Australia.

    • Ted Edkins

  93. Department of Multicultural Health, University of Sydney, New South Wales 2052, Australia.

    • Maurice Eisenbruch

  94. Tissue Pathology, Institute of Medical & Veterinary Science, Adelaide, South Australia 5000, Australia.

    • Gelareh Farshid

  95. Family Cancer Clinic, Monash Medical Centre, Clayton, Victoria 3168, Australia.

    • Susan Fawcett

  96. Faculty of Medicine, Royal North Shore Hospital, Vindin House, St Leonards, New South Wales 2065, Australia.

    • Michael Field

  97. Department of Haematology, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.

    • Frank Firgaira
    • , Scott Grist
    •  & Ram Seshadri

  98. Eskitis Institute of Cell & Molecular Therapies, School of Biomolecular and Biomedical Sciences, Griffith University, Nathan, Queensland 4111, Australia.

    • Jean Fleming

  99. Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, Waratah, New South Wales 2298, Australia.

    • John Forbes

  100. Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

    • Michael Friedlander

  101. Victorian Clinical Genetics Service, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia.

    • Clara Gaff
    •  & Mac Gardner

  102. Queensland Clinical Genetic Service, Royal Children’s Hospital, Bramston Terrace, Herston, Queensland 4020, Australia.

    • Mike Gattas

  103. Clinical Biochemistry Unit, Canterbury Health Labs, PO Box 151, Christchurch 8140, New Zealand.

    • Peter George

  104. Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne Street, Carlton, Victoria 3053, Australia.

    • Graham Giles

  105. Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.

    • Grantley Gill

  106. Genetic Services of WA, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Western Australia 6008, Australia.

    • Jack Goldblatt
    • , Sharron Townshend
    •  & Ian Walpole

  107. Wollongong Hereditary Cancer Clinic, Wollongong Public Hospital, Private Mail Bag 8808, South Coast Mail Centre, New South Wales 2521, Australia.

    • Sian Greening

  108. Department of Medical Genetics, Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

    • Eric Haan
    •  & Graeme Suthers

  109. Familial Cancer Clinic, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia.

    • Marion Harris
    • , Michael McKay
    • , Gillian Mitchell
    •  & Mary Ann Young

  110. Breast and Ovarian Cancer Genetics, Monash Medical Centre, 871 Centre Road, Bentleigh East, Victoria 3165, Australia.

    • Stewart Hart

  111. Centre for Molecular Environmental, Genetic & Analytic Epidemiology, University of Melbourne, Melbourne, Victoria 3010, Australia.

    • John Hopper
    • , Richard Osborne
    •  & Dorota Gertig

  112. School of Population Health, The University of Melbourne, 723 Swanston Street, Carlton, Victoria 3053, Australia.

    • Mark Jenkins

  113. Medical Oncology, Westmead Hospital, Westmead, New South Wales 2145, Australia.

    • Rick Kefford

  114. Familial Cancer Service, Department of Medicine, Westmead Hospital, Westmead, New South Wales 2145, Australia.

    • Judy Kirk
    •  & Jennifer Leary

  115. Breast Endocrine and Surgical Unit, Royal Adelaide Hospital, North Terrace, South Australia 5000, Australia.

    • James Kollias

  116. Molecular Pathology Department, Southern Cross Pathology, Monash Medical Centre, Clayton, Victoria 3168, Australia.

    • Sergey Kovalenko

  117. Molecular and Cellular Pathology, The University of Queensland, Herston, Queensland 4006, Australia.

    • Sunil Lakhani

  118. Department of Psychological Medicine, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.

    • Jacqueline Lim
    • , Christopher Tennant
    • , Arto Mannermaa
    • , Veli-Matti Kosma
    • , Vesa Kataja
    •  & Jaana Hartikainen

  119. Breast Cancer Laboratory, Walter and Eliza Hall Institute, PO Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

    • Geoff Lindeman
    • , Arto Mannermaa
    • , Veli-Matti Kosma
    •  & Jaana Hartikainen

  120. Medical Oncology and Clinical Haematology Unit, Western Hospital, Footscray, Victoria 3011, Australia.

    • Lara Lipton
    •  & Vesa Kataja

  121. WA Centre for Cancer, Edith Cowan University, Churchlands, Western Australia 6018, Australia.

    • Liz Lobb

  122. Department of Psychological Medicine, University of Sydney, New South Wales 2006, Australia.

    • Mariette Maclurcan
    •  & Melanie Price

  123. Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.

    • Deborah Marsh

  124. Cancer Epidemiology Research Unit, NSW Cancer Council, 153 Dowling Street, Woolloomooloo, New South Wales 2011, Australia.

    • Margaret McCredie

  125. Department of Oncology, St Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.

    • Sue Anne McLachlan

  126. School of Public Health, Queensland University of Technology, Victoria Park, Kelvin Grove, Queensland 4059, Australia.

    • Beth Newman

  127. St Vincent’s Breast Clinic, PO Box 4751, Toowoomba, Queensland 4350, Australia.

    • Imelda O’Loughlin
    • , Graham Warren
    •  & Elizabeth Watson

  128. Radiation Oncology, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia.

    • Lester Peters

  129. Genetic Services, Auckland Hospital, Private Bag 92024, Auckland 1142, New Zealand.

    • Jeanne Reeve
    •  & Ingrid Winship

  130. Cancer Genetics Laboratory, University of Otago, PO Box 56, Dunedin 9054, New Zealand.

    • Tony Reeve

  131. Department of Cytogenetics and Molecular Genetics, Women and Children’s Hospital, Adelaide, South Australia 5006, Australia.

    • Robert Richards

  132. Hancock Family Breast Cancer Foundation, PO Locked Bag 2, West Perth, Western Australia 6005, Australia.

    • Gina Rinehart

  133. Oncology Service, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand.

    • Bridget Robinson

  134. Molecular Pathology Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia.

    • Barney Rudzki

  135. Section of Cytology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales 2145, Australia.

    • Elizabeth Salisbury

  136. School of Surgery and Pathology, QE11 Medical Centre, M block 2nd Floor, Nedlands, Western Australia 6907, Australia.

    • Christobel Saunders

  137. South View Clinic, Suite 13, Level 3 South Street, Kogarah, New South Wales 2217, Australia.

    • Elizabeth Scott

  138. Department of Obstetrics and Gynaecology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

    • Andrew Shelling

  139. Department of Radiology, Royal Perth Hospital, Box X2213, Perth 6011, Western Australia, Australia.

    • Donna Taylor

  140. Murdoch Institute, Royal Children’s Hospital, Parkville, Victoria 3050, Australia.

    • Deon Venter

  141. Molecular Genetics of Cancer Division, Walter & Eliza Hall Medical Research Institute, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

    • Jane Visvader

  142. Department of Medical Oncology, St Vincents Hospital, Darlinghurst, New South Wales 2010, Australia.

    • Robin Ward

  143. Cabrini Hospital, 183 Wattletree Road, Malvern, Victoria 3144, Australia.

    • Bev Warner

  144. Family Cancer Clinic, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.

    • Rachael Williams

  145. Medical Psychology Research Unit, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.

    • Judy Wilson

  146. Cancer Genomics & Biochemistry Laboratory, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia.

    • David Bowtell

  147. Obstetrics & Gynaecology, Westmead Hospital, University of Sydney, New South Wales 2006, Australia.

    • Anna deFazio

  148. Lists of consortia participants and affiliations appear after author affiliations.

Consortia

  1. The SEARCH collaborators

  2. kConFab

  3. AOCS Management Group

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Douglas F. Easton.

Supplementary information

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    Supplementary Information 3

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    Supplementary Information 2

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DOI

https://doi.org/10.1038/nature05887

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