GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer (original) (raw)

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Acknowledgements

We thank all the individuals who took part in this study and all the researchers, clinicians and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). 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 (PPD/RPCI.07). The scientific development and funding for this project were supported in part by the Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found on the website (see URLs).

Author information

Author notes

1. Paul D P Pharoah, Ya-Yu Tsai, Susan J Ramus, Catherine M Phelan and Joellen M Schildkraut: These authors contributed equally to this work.
2. Joellen M Schildkraut and Thomas A Sellers: These authors jointly directed this work.

Authors and Affiliations

1. Department of Oncology, The Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
   Paul D P Pharoah, Jonathan P Tyrer, Honglin Song, Ed Dicks, Qi Guo & Douglas F Easton
2. Department of Public Health and Primary Care, The Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
   Paul D P Pharoah, Joe Dennis & Douglas F Easton
3. Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida, USA
   Ya-Yu Tsai, Catherine M Phelan, Melissa Buckley, Greg Bloom, Renato S Carvalho, Y Anne Chen, Zhihua Chen, David Fenstermacher, Anxhela Gjyshi, Jenny Permuth-Wey, Xiaotao Qu, Alvaro N A Monteiro & Thomas A Sellers
4. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA
   Susan J Ramus, Kate Lawrenson, Howard Shen, Rod Karevan, Nathan Lee, Janet Lee, Malcolm C Pike, David van den Berg, Anna H Wu, Celeste L Pearce & Simon A Gayther
5. Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
   Ellen L Goode, Brooke L Fridley, Mine S Cicek & Robert A Vierkant
6. Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
   Rachel Weber & Joellen M Schildkraut
7. Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota, USA
   Melissa C Larson & Sebastian M Armasu
8. Centre Technologiques, McGill University, Montreal, Quebec, Canada
   Daniel C Tessier, François Bacot & Daniel Vincent
9. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
   Daniel C Tessier, François Bacot & Daniel Vincent
10. Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
    Julie M Cunningham & Vijayalakshmi Shridhar
11. Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Medical Centre, Nijmegen, The Netherlands
    Katja K Aben & Lambertus A Kiemeney
12. Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands
    Katja K Aben & Lambertus A Kiemeney
13. Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California–Irvine, Irvine, California, USA
    Hoda Anton-Culver & Argyrios Ziogas
14. N.N. Aleksandrov Byelorussian Institute for Oncology and Medical Radiology, Minsk, Belarus
    Natalia Antonenkova
15. Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia
    Laura Baglietto, Graham Giles & Gianluca Severi
16. Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia
    Laura Baglietto, Graham Giles & Gianluca Severi
17. The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
    Elisa V Bandera & Lorna Rodriguez-Rodriguez
18. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
    Matthias W Beckmann, Peter A Fasching & Alexander Hein
19. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Michael J Birrer
20. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
    Michael J Birrer
21. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
    Natalia Bogdanova & Thilo Dörk
22. Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
    James D Brenton
23. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
    Louise A Brinton, Nicolas Wentzensen & Hannah P Yang
24. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
    Angela Brooks-Wilson
25. Department of Surgery and Cancer, Imperial College London, London, UK
    Robert Brown & James Flanagan
26. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
    Ralf Butzow
27. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland
    Ralf Butzow, Arto Leminen, Heli Nevanlinna & Liisa M Pelttari
28. Research Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    Ian Campbell
29. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
    Ian Campbell
30. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
    Michael E Carney, Galina Lurie, Pamela J Thompson & Marc T Goodman
31. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
    Jenny Chang-Claude, Stefan Nickels & Anja Rudolph
32. Division of Cancer Etiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
    Wong-Ho Chow
33. Department of Microbiology and Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA
    Gerhard Coetzee & Houtan Noushmehr
34. Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA
    Linda S Cook
35. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Daniel W Cramer, Kathryn L Terry & Allison F Vitonis
36. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
    Daniel W Cramer, Elizabeth M Poole, Kathryn L Terry & Shelley S Tworoger
37. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
    Cezary Cybulski, Jacek Gronwald, Anna Jakubowska & Jan Lubiński
38. Department of Molecular Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
    Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk & Iwona K Rzepecka
39. Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology, Leuven Cancer Institute, Leuven, Belgium
    Evelyn Despierre, Sandrina Lambrechts & Ignace Vergote
40. Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA
    Jennifer A Doherty
41. Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
    Andreas du Bois, Philipp Harter & Florian Heitz
42. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft, Essen, Germany
    Andreas du Bois, Philipp Harter & Florian Heitz
43. Department of Gynecology, Jena University Hospital, Jena, Germany
    Matthias Dürst & Ingo Runnebaum
44. Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
    Diana Eccles
45. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Robert Edwards & Francesmary Modugno
46. Women's Cancer Program, Magee-Womens Research Institute, Pittsburg, Pennsylvania, USA
    Robert Edwards
47. Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
    Arif B Ekici
48. 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 & Gottfried E Konecny
49. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
    Yu-Tang Gao
50. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK
    Montserrat Garcia-Closas
51. Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
    Montserrat Garcia-Closas
52. Gynaecological Cancer Research Centre, University College London Elizabeth Garrett Anderson Institute for Women's Health, London, UK
    Aleksandra Gentry-Maharaj & Usha Menon
53. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
    Graham Giles
54. Gynecological Oncology Unit, The Royal Marsden Hospital, London, UK
    Martin Gore
55. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
    Mari K Halle, Camilla Krakstad, Helga B Salvesen & Elisabeth Wik
56. Department of Clinical Medicine, University of Bergen, Bergen, Norway
    Mari K Halle, Camilla Krakstad, Helga B Salvesen & Elisabeth Wik
57. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
    Peter Hillemanns
58. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA
    Maureen Hoatlin
59. Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
    Estrid Høgdall, Allan Jensen & Susanne Krüger Kjaer
60. Department of Pathology, Molecular Unit, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
    Estrid Høgdall
61. Department of Obstetrics and Gynecology, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark
    Claus K Høgdall, Susanne Krüger Kjaer & Lene Lundvall
62. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
    Satoyo Hosono, Keitaro Matsuo & Kazuo Tajima
63. Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
    Kimberly R Kalli
64. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
    Beth Y Karlan
65. Department of Population Health Research, Alberta Health Services–Cancer Care, Calgary, Alberta, Canada
    Linda E Kelemen
66. Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada
    Linda E Kelemen
67. Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands
    Lambertus A Kiemeney
68. Vesalius Research Center, University of Leuven, Leuven, Belgium
    Diether Lambrechts
69. Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
    Nhu D Le
70. Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
    Boon Kiong Lim & Yin Ling Woo
71. The Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
    Jolanta Lissowska
72. Department of Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands
    Leon F A G Massuger & Anne M van Altena
73. Department of Health Research and Policy–Epidemiology, Stanford University School of Medicine, Stanford, California, USA
    Valerie McGuire, Weiva Sieh & Alice S Whittemore
74. Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
    John R McLaughlin
75. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
    John R McLaughlin
76. Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Francesmary Modugno
77. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA
    Kirsten B Moysich & Kunle Odunsi
78. Department of Gynecologic Oncology, Aichi Cancer Center Central Hospital, Nagoya, Japan
    Toru Nakanishi
79. Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
    Steven A Narod
80. The University of Texas School of Public Health, Houston, Texas, USA
    Roberta B Ness
81. University of Southern California Epigenome Center, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA
    Houtan Noushmehr & Hui Shen
82. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
    Sara Olson, Irene Orlow & Malcolm C Pike
83. The Beatson West of Scotland Cancer Centre, Glasgow, UK
    James Paul
84. Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA
    Tanja Pejovic
85. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
    Tanja Pejovic
86. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
    Elizabeth M Poole & Shelley S Tworoger
87. Department of Epidemiology and Public Health, Yale University School of Public Health and School of Medicine, New Haven, Connecticut, USA
    Harvey A Risch
88. Department of Epidemiology, University of Washington, Seattle, Washington, USA
    Mary Anne Rossing
89. Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    Mary Anne Rossing
90. Institut für Humangenetik, Wiesbaden, Germany
    Ira Schwaab
91. Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Xiao-Ou Shu & Wei Zheng
92. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Xiao-Ou Shu & Wei Zheng
93. Department of Pathology, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, Victoria, Australia
    Melissa C Southey
94. Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
    Paul Spellman
95. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
    Soo-Hwang Teo & Famida Zulkifli
96. University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
    Soo-Hwang Teo & Famida Zulkifli
97. Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University, Warsaw, Poland
    Agnieszka Timorek
98. Department of Obstetrics and Gynaecology, Brodnowski Hospital, Warsaw, Poland
    Agnieszka Timorek
99. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany
    Shan Wang-Gohrke
100. Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA
     Boris Winterhoff
101. Department of Epidemiology and Biostatistics, Karolinska Istitutet, Stockholm, Sweden
     Per Hall
102. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA
     Andrew Berchuck
103. Cancer Division, Queensland Institute of Medical Research, Herston, Queensland, Australia
     Georgia Chenevix-Trench
104. Department of Statistics, Duke University, Durham, North Carolina, USA
     Edwin Iversen
105. Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute, Durham, North Carolina, USA
     Joellen M Schildkraut

Authors

1. Paul D P Pharoah
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2. Ya-Yu Tsai
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3. Susan J Ramus
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4. Catherine M Phelan
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5. Ellen L Goode
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6. Kate Lawrenson
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7. Melissa Buckley
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8. Brooke L Fridley
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9. Jonathan P Tyrer
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10. Howard Shen
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11. Rachel Weber
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12. Rod Karevan
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13. Melissa C Larson
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14. Honglin Song
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15. Daniel C Tessier
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16. François Bacot
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17. Daniel Vincent
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18. Julie M Cunningham
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19. Joe Dennis
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20. Ed Dicks
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21. Katja K Aben
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22. Hoda Anton-Culver
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23. Natalia Antonenkova
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24. Sebastian M Armasu
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25. Laura Baglietto
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26. Elisa V Bandera
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27. Matthias W Beckmann
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28. Michael J Birrer
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29. Greg Bloom
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30. Natalia Bogdanova
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31. James D Brenton
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32. Louise A Brinton
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33. Angela Brooks-Wilson
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37. Michael E Carney
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38. Renato S Carvalho
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39. Jenny Chang-Claude
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40. Y Anne Chen
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41. Zhihua Chen
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42. Wong-Ho Chow
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43. Mine S Cicek
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44. Gerhard Coetzee
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47. Cezary Cybulski
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48. Agnieszka Dansonka-Mieszkowska
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49. Evelyn Despierre
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50. Jennifer A Doherty
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51. Thilo Dörk
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52. Andreas du Bois
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53. Matthias Dürst
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54. Diana Eccles
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55. Robert Edwards
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Consortia

Australian Cancer Study

Australian Ovarian Cancer Study Group

Contributions

Writing group: P.D.P.P., Y.-Y.T., C.M.P., S.J.R., J.M.S., T.A.S., B.L.F., E.L.G., A.N.A.M. and S.A.G. All authors read and approved the final manuscript. Provision of samples and data from contributing studies: K.L., M.P., J.P.T., H. Shen, R.W., R.K., M.C.L., H. Song, D.C.T., F.B., D.V., J.M.C., J.D., E. Dicks, K.K.A., H.A.-C., N.A., S.M.A., L.B., E.V.B., M.W.B., M.J.B., G.B., N.B., J.D.B., L.A.B., A.B.-W., R. Brown, R. Butzow, I.C., M.E.C., R.S.C., J.C.-C., Y.A.C., Z.C., A.D.-M., E. Despierre, J.A.D., T.D., A.d.B., M.D., D.E., R.E., A.B.E., P.A.F., D.F., J.F., Y.-T.G., M.G.-C., A.G.-M., G.G., A.G., M.G., J.G., Q.G., M.K.H., P. Harter, A.H., F.H., P. Hillemanns, M.H., E.H., C.K.H., S.H., A. Jakubowska, A. Jensen, K.R.K., B.Y.K., L.E.K., L.A.K., S.K.K., G.E.K., C.K., J.K., D.L., S.L., N.D.L., N.L., J. Lee, A.L., B.K.L., J. Lissowska, J. Lubinński, L.L., G.L., L.F.A.G.M., K.M., V.M., J.R.M., U.M., F.M., K.B.M., T.N., S.A.N., R.B.N., H. Nevanlinna, S.N., H. Noushmehr, K.O., S.O., I.O., J.P., T.P., L.M.P., J.P.-W., M.C.P., E.M.P., X.Q., H.A.R., L.R.-R., M.A.R., A.R., I.R., I.K.R., H.B.S., I.S., G.S., H. Shen, V.S., X.-O.S., W.S., M.C.S., P.S., K.T., S.-H.T., K.L.T., P.J.T., A.T., S.S.T., A.M.v.A., D.v.d.B., I.V., R.A.V., A.F.V., S.W.-G., N.W., A.S.W., E.W., B.W., Y.L.W., A.H.W., H.P.Y., W.Z., A.Z., F.Z., M.T.G., P. Hall, D.F.E., C.L.P., A.B., G.C.-T., E.I. and J.M.S. Bioinformatics and data management: J.D., E. Dicks, Z.C. and R.W. Data analysis: J.P.T., Q.G., Y.-Y.T. and B.L.F. Preparation of samples for genotyping: S.J.R. and C.M.P. Genotyping: J.M.C., D.C.T., F.B. and D.V. Functional analyses: S.A.G., M.B., A.N.A.M., B.L.F., K.L., H. Shen, E.L.G., S.J.R., Y.A.C. and M.L.C.

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Correspondence toPaul D P Pharoah.

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The authors declare no competing financial interests.

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A list of members is provided in the Supplementary Note.

A list of members is provided in the Supplementary Note.

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Pharoah, P., Tsai, YY., Ramus, S. et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.Nat Genet 45, 362–370 (2013). https://doi.org/10.1038/ng.2564

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• Received: 11 May 2012
• Accepted: 30 January 2013
• Published: 27 March 2013
• Issue Date: April 2013
• DOI: https://doi.org/10.1038/ng.2564