Letter | Published:

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

Nature Genetics volume 42, pages 874879 (2010) | Download Citation

Abstract

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2)1. Here, we report on nine additional candidate loci (defined as having P ≤ 10−4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10−8 (8q24, P = 8.0 × 10−15 and 2q31, P = 3.8 × 10−14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10−8 and 17q21, P = 1.4 × 10−7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996–1000 (2009).

  2. 2.

    et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).

  3. 3.

    et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).

  4. 4.

    et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 41, 1058–1060 (2009).

  5. 5.

    et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat. Genet. 40, 631–637 (2008).

  6. 6.

    et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl. Cancer Inst. 100, 962–966 (2008).

  7. 7.

    et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).

  8. 8.

    et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 5, e1000597 (2009).

  9. 9.

    et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).

  10. 10.

    & Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31. Int. J. Oncol. 23, 541–547 (2003).

  11. 11.

    et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

  12. 12.

    et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

  13. 13.

    , , , & TCDD-inducible poly(ADP-ribose) polymerase: a novel response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem. Biophys. Res. Commun. 289, 499–506 (2001).

  14. 14.

    & New molecular concepts and targets in acute myeloid leukemia. Curr. Opin. Hematol. 15, 82–87 (2008).

  15. 15.

    , , , & HOX gene clusters are hotspots of de novo methylation in CpG islands of human lung adenocarcinomas. Oncogene 21, 3659–3662 (2002).

  16. 16.

    , , & Discovery of epigenetically silenced genes by methylated DNA immunoprecipitation in colon cancer cells. Cancer Res. 67, 11481–11486 (2007).

  17. 17.

    et al. Transduction of HOXD3-antisense into human melanoma cells results in decreased invasive and motile activities. Clin. Exp. Metastasis 19, 503–511 (2002).

  18. 18.

    , & SKAP associates with kinetochores and promotes the metaphase-to-anaphase transition. Cell Cycle 8, 2819–2827 (2009).

  19. 19.

    , , , & SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1. Mol. Immunol. 45, 510–522 (2008).

  20. 20.

    et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. advance online publication, doi:10.1038/ng.666 (19 September 2010).

  21. 21.

    et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin. Cancer Res. 10, 2473–2481 (2004).

  22. 22.

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  23. 23.

    et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat. Genet. 40, 623–630 (2008).

  24. 24.

    et al. FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum. Mol. Genet. 18, 1692–1703 (2009).

  25. 25.

    , , & Estimating local ancestry in admixed populations. Am. J. Hum. Genet. 82, 290–303 (2008).

  26. 26.

    & Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

  27. 27.

    & Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).

  28. 28.

    et al. A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitro. Lab. Invest. 84, 923–931 (2004).

  29. 29.

    et al. Senescent fibroblasts promote neoplastic transformation of ovarian epithelial cells in a three-dimensional model of early stage ovarian cancer. Neoplasia 12, 317–325 (2010).

  30. 30.

    et al. In vitro three-dimensional modelling of human ovarian surface epithelial cells. Cell Prolif. 42, 385–393 (2009).

Download references

Acknowledgements

We thank all the individuals who took part in this study. We thank all the researchers, clinicians and administrative staff who have made possible the many studies contributing to this work. In particular, we thank A. Ryan and J. Ford (UKO); J. Morrison, P. Harrington and the SEARCH team (SEA); U. Eilber and T. Koehler (GER); D. Bowtell, A. deFazio, D. Gertig, A. Green, P. Parsons, N. Hayward and D. Whiteman (AUS); L. Gacucova (HMO); S. Haubold, P. Schürmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); and L. Brinton, M. Sherman, A. Hutchinson, N. Szeszenia- Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL1). The genotyping and data analysis for this study was supported by a project grant from Cancer Research UK. We acknowledge the computational resources provided by the University of Cambridge (CamGrid). This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith.

The MAL study is supported by grants from Mermaid 1, the Danish Cancer Society and the National Cancer Institute, Bethesda, Maryland, USA (R01-CA-61107). The MAY study and the phase 3 and combined analyses were supported by the US National Institutes of Health, National Cancer Institute grants R01-CA-122443 and funding from the Mayo Foundation. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, Department of Health and Human Services. The Fox Chase Cancer Center ovarian cancer study, part of the National Cancer Institute collaboration, is supported by an Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50 CA083638). The NCO study is supported by the US National Institutes of Health, National Cancer Institute grant R01-CA-76016. The SEA study is funded by a programme grant from Cancer Research UK. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre for subject recruitment. The TBO study was supported by the US National Institutes of Health (R01-CA106414); the American Cancer Society (CRTG-00-196-01-CCE); and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD17-98-1-8659). The TOR study was supported by grants from the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and the US National Institutes of Health (R01-CA-63682 and R01-CA-63678). Additional support for the TOR, NCO, MAY, TBO and NCI studies was provided by the University of California, Irvine grant R01-CA-114343. The UCI study is supported by the US National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal and the OAK Foundation. Some of this work was undertaken at University College London Hospital/University College London, who received a proportion of funding from the Department of Health's National Institutes for Health Research Biomedical Research Centre funding scheme. We particularly thank I. Jacobs, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The AUS study is supported by the National Health and Medical Research Council of Australia (199600), US Army Medical Research and Materiel Command under DAMD17-01-1-0729 (award no. W81XWH-06-1-0220) and the Cancer Council Tasmania and Cancer Foundation of Western Australia. G.C.-M.T. and P.M.W. are Research Fellows of the National Health and Medical Research Council. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, A. deFazio, G.C.-T., D.G., A.K.G. and P.M.W.) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study (ACS) Management Group comprises P.D.P.P., P.M.W., A. Green, N. Hayward and D. Whiteman. The BAV study is supported by the ELAN Foundation and Erlangen University Hospital. The BEL study is supported by the National Cancer Plan-Action 29 for the support of Translational Research. The DOV study (Seattle Diseases of the Ovary) was supported by the US National Institutes of Health grants R01-CA-112523 and R01-CA-87538. The GER study was supported by the German Federal Ministry of Education and Research of Germany, the Programme of Clinical Biomedical Research (01 GB 9401), and the genotyping was supported in part by the state of Baden-Württemberg through the Medical Faculty, University of Ulm (P.685). Data management was supported by the German Cancer Research Center. The HAW study was supported by the US Public Health Service grant R01-CA-58598 and contracts N01-CN-55424, N01-PC-67001 and N01-PC-35137 from the National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. Funding for the USC study was received from the California Cancer Research Program grants 00-01389V-20170 and 2110200, US Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148 and the California Department of Health Services sub-contract 050-E8709 as part of its statewide cancer reporting program (University of Southern California). The HJO study gratefully acknowledges the contribution of F. Kramer and W. Zheng to the recruitment of subjects at Hannover Medical School. The HMO study gratefully acknowledges the help of L. Gacucova in sample preparation. The HOC study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society.

Author information

Author notes

    • Ellen L Goode
    • , Georgia Chenevix-Trench
    • , Honglin Song
    •  & Susan J Ramus

    These authors contributed equally to this work.

Affiliations

  1. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Ellen L Goode
    • , Robert A Vierkant
    • , Melissa C Larson
    •  & Brooke L Fridley
  2. The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Australia.

    • Georgia Chenevix-Trench
    • , Jonathan Beesley
    • , Penelope M Webb
    •  & Xiaoqing Chen
  3. Cancer Research United Kingdom, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Honglin Song
    • , Anne Stafford
    • , Jonathan Tyrer
    •  & Patricia Harrington
  4. Department of Gynaecological Oncology, University College London, Elizabeth Garrett Anderson (EGA) Institute for Women's Health, London, UK.

    • Susan J Ramus
    • , Maria Notaridou
    • , Kate Lawrenson
    • , Martin Widschwendter
    • , Aleksandra Gentry-Maharaj
    • , Usha Menon
    •  & Simon A Gayther
  5. The Juliane Marie Centre, Department of Gynecology and Obstetrics, Rigshospitalet, Copenhagen, Denmark.

    • Susanne K Kjaer
    •  & Ingo Runnebaum
  6. Department of Virus, Hormones and Cancer Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.

    • Susanne K Kjaer
    •  & Ingo Runnebaum
  7. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Michael J Birrer
  8. Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Andrew Berchuck
    •  & Joellen Schildkraut
  9. Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, London, UK.

    • Ian Tomlinson
  10. Department of Epidemiology, Biostatistics and Health Technology Assessment (HTA), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  11. Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, New Mexico, USA.

    • Linda S Cook
    •  & Jan Lubinski
  12. Alberta Health Services-Cancer Care, Calgary, Alberta, Canada.

    • Linda S Cook
  13. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

    • Jacek Gronwald
    • , Anna Jakubowska
    •  & Krzysztof Medrek
  14. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

    • Montserrat Garcia-Closas
    • , Hannah Yang
    •  & Nicolas Wentzensen
  15. The Royal Marsden Hospital, Gynecological Oncology Unit, Fulham Road, London, UK.

    • Martin E Gore
  16. Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia.

    • Ian Campbell
  17. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.

    • Ian Campbell
  18. Division of Epidemiology and Biostatistics, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA.

    • Alice S Whittemore
    • , Ashley N Molina
    •  & Barbara N Davila
  19. University of South Florida, Pediatrics Epidemiology Center, College of Medicine, Tampa, Florida, USA.

    • Rebecca Sutphen
    • , Weiva Sieh
    •  & Valerie McGuire
  20. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Catherine Phelan
    • , Ann Chen
    • , Ya-Yu Tsai
    • , Zhihua Chen
    •  & Thomas A Sellers
  21. Department of Epidemiology, School of Medicine, University of California, Irvine, California.

    • Hoda Anton-Culver
    •  & Argyrios Ziogas
  22. University of Southern California, Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA.

    • Celeste Leigh Pearce
    • , Anna H Wu
    • , Daniel O Stram
    •  & Malcolm C Pike
  23. Vesalius Research Center, Flanders interuniversity Institute of Biotechnology (VIB) and K.U. Leuven, Belgium.

    • Diether Lambrechts
  24. Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Mary Anne Rossing
    •  & Jennifer Doherty
  25. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jenny Chang-Claude
    •  & Rebecca Hein
  26. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Kirsten B Moysich
  27. University of Hawaii, Cancer Research Center, Honolulu, Hawaii, USA.

    • Marc T Goodman
    • , Galina Lurie
    • , Michael E Carney
    •  & Pamela J Thompson
  28. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.

    • Thilo Dörk
    •  & Peter Hillemanns
  29. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.

    • Heli Nevanlinna
    • , Arto Leminen
    •  & Tuomas Heikkinen
  30. University of Texas School of Public Health, Houston, Texas, USA.

    • Roberta B Ness
  31. deCODE Genetics, Reykjavik, Iceland.

    • Thorunn Rafnar
    • , Kari Stefansson
    • , Patrick Sulem
    •  & Sören Besenbacher
  32. The Juliane Marie Centre, Department of Gynecology and Obstetrics, Rigshospitalet, Copenhagen, Denmark.

    • Claus Hogdall
  33. Department of Virus, Hormones and Cancer Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.

    • Estrid Hogdall
  34. Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Julie M Cunningham
  35. Women's Cancer Program, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Andrew K Godwin
  36. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Daniel W Cramer
  37. National Institutes of Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Dena Hernandez
  38. Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Douglas Levine
  39. MD Anderson Cancer Center, Houston, Texas, USA.

    • Karen Lu
  40. Department of Statistics, Duke University, Durham, North Carolina, USA.

    • Edwin S Iversen
  41. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Rachel T Palmieri
  42. Molecular and Population Genetics Team, The Institute of Cancer Research, Royal Cancer Hospital, London, UK.

    • Richard Houlston
  43. Department of Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Anne M van Altena
    •  & Leon F A G Massuger
  44. Comprehensive Cancer Centre East, Nijmegen, The Netherlands.

    • Katja K H Aben
  45. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Angela Brooks-Wilson
  46. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

    • Angela Brooks-Wilson
  47. Alberta Health Services-Cancer Care, Calgary, Alberta, Canada.

    • Linda E Kelemen
  48. Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Nhu D Le
  49. Cancer Research United Kingdom Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Douglas F Easton
  50. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Kelly L Bolton
  51. University of Southampton School of Medicine, Wessex Clinical Genetics Service Princess Anne Hospital, Southampton, UK.

    • Diana Eccles
  52. West Coast Gynecologic Oncology, Clearwater, Florida, USA.

    • Hector Arango
  53. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Harvey A Risch
  54. Cancer Care Ontario, Toronto, Ontario, Canada.

    • John McLaughlin
  55. Women′s College Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • Steven A Narod
  56. Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina, USA.

    • Wendy Brewster
  57. Peter MacCallum Cancer Institute, Melbourne, Australia.

  58. Institute of Human Genetics, Friedrich Alexander University Erlangen Nuremberg, Erlangen, Germany.

    • Arif B Ekici
  59. University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany.

    • Falk C Thiel
  60. Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Matthias W Beckmann
    •  & Jolanta Lissowska
  61. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  62. Department of Gynaecologic Oncology, University Hospitals Leuven, Leuven, Belgium.

    • Evelyn Despierre
    • , Frederic Amant
    •  & Ignace Vergote
  63. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.

    • Shan Wang-Gohrke
  64. Clinics of Obstetrics and Gynaecology, Friedrich Schiller University, Jena, Germany.

    • Matthias Dürst
  65. Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.

    • Natalia Antonenkova
  66. Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.

    • Natalia Bogdanova
  67. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.

    • Natalia Bogdanova
  68. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.

    • Ralf Butzow
  69. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.

    • Ralf Butzow
  70. Cancer Research United Kingdom Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Paul D P Pharoah
  71. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Paul D P Pharoah

Consortia

  1. The Wellcome Trust Case-Control Consortium

    A full list of members is provided in the Supplementary Note.

  2. The Australian Cancer Study (Ovarian Cancer)

    1. The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital
  3. The Australian Ovarian Cancer Study Group

    1. Peter MacCallum Cancer Institute
  4. the Ovarian Cancer Association Consortium (OCAC)

Authors

  1. Search for Ellen L Goode in:

  2. Search for Georgia Chenevix-Trench in:

  3. Search for Honglin Song in:

  4. Search for Susan J Ramus in:

  5. Search for Maria Notaridou in:

  6. Search for Kate Lawrenson in:

  7. Search for Martin Widschwendter in:

  8. Search for Robert A Vierkant in:

  9. Search for Melissa C Larson in:

  10. Search for Susanne K Kjaer in:

  11. Search for Michael J Birrer in:

  12. Search for Andrew Berchuck in:

  13. Search for Joellen Schildkraut in:

  14. Search for Ian Tomlinson in:

  15. Search for Lambertus A Kiemeney in:

  16. Search for Linda S Cook in:

  17. Search for Jacek Gronwald in:

  18. Search for Montserrat Garcia-Closas in:

  19. Search for Martin E Gore in:

  20. Search for Ian Campbell in:

  21. Search for Alice S Whittemore in:

  22. Search for Rebecca Sutphen in:

  23. Search for Catherine Phelan in:

  24. Search for Hoda Anton-Culver in:

  25. Search for Celeste Leigh Pearce in:

  26. Search for Diether Lambrechts in:

  27. Search for Mary Anne Rossing in:

  28. Search for Jenny Chang-Claude in:

  29. Search for Kirsten B Moysich in:

  30. Search for Marc T Goodman in:

  31. Search for Thilo Dörk in:

  32. Search for Heli Nevanlinna in:

  33. Search for Roberta B Ness in:

  34. Search for Thorunn Rafnar in:

  35. Search for Claus Hogdall in:

  36. Search for Estrid Hogdall in:

  37. Search for Brooke L Fridley in:

  38. Search for Julie M Cunningham in:

  39. Search for Weiva Sieh in:

  40. Search for Valerie McGuire in:

  41. Search for Andrew K Godwin in:

  42. Search for Daniel W Cramer in:

  43. Search for Dena Hernandez in:

  44. Search for Douglas Levine in:

  45. Search for Karen Lu in:

  46. Search for Edwin S Iversen in:

  47. Search for Rachel T Palmieri in:

  48. Search for Richard Houlston in:

  49. Search for Anne M van Altena in:

  50. Search for Katja K H Aben in:

  51. Search for Leon F A G Massuger in:

  52. Search for Angela Brooks-Wilson in:

  53. Search for Linda E Kelemen in:

  54. Search for Nhu D Le in:

  55. Search for Anna Jakubowska in:

  56. Search for Jan Lubinski in:

  57. Search for Krzysztof Medrek in:

  58. Search for Anne Stafford in:

  59. Search for Douglas F Easton in:

  60. Search for Jonathan Tyrer in:

  61. Search for Kelly L Bolton in:

  62. Search for Patricia Harrington in:

  63. Search for Diana Eccles in:

  64. Search for Ann Chen in:

  65. Search for Ashley N Molina in:

  66. Search for Barbara N Davila in:

  67. Search for Hector Arango in:

  68. Search for Ya-Yu Tsai in:

  69. Search for Zhihua Chen in:

  70. Search for Harvey A Risch in:

  71. Search for John McLaughlin in:

  72. Search for Steven A Narod in:

  73. Search for Argyrios Ziogas in:

  74. Search for Wendy Brewster in:

  75. Search for Aleksandra Gentry-Maharaj in:

  76. Search for Usha Menon in:

  77. Search for Anna H Wu in:

  78. Search for Daniel O Stram in:

  79. Search for Malcolm C Pike in:

  80. Search for Jonathan Beesley in:

  81. Search for Penelope M Webb in:

Contributions

P.D.P.P., S.A.G., D.F.E. and A.B. designed the overall study and obtained financial support. P.D.P.P., S.A.G., S.J.R. and H.S. coordinated the studies used in phase 1 and phase 2. H.S., G.C.-T. and E.L.G. coordinated phase 3. J.T. and H.S. conducted primary phase 1 and phase 2 analyses and phase 3 SNP selection. H.S., J.B. and J.M.C. conducted phase 3 genotyping, R.A.V. and M.C.L. conducted phase 3 and combined data statistical analyses, and S.A.G., M.N. and K. Lawrenson designed and performed 'functional' analysis of candidate genes. E.L.G. and S.A.G. drafted the manuscript with substantial input from G.C.-T., H.S., S.J.R., T.A.S. and P.D.P.P. The remaining authors coordinated contributing studies, and all authors contributed to the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Simon A Gayther.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–11 and Supplementary Figures 1–3

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.668

Further reading