Article open access publication

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 9, 1, 2018

DOI:10.1038/s41467-018-04109-8, Dimensions: pub.1104381151, PMC: PMC5995836, PMID: 29892050,

Authors

Benlloch, Sara (1) (2)
Goh, Chee (1)
Muir, Kenneth (8) (9)
Batra, Jyotsna (13) (14)
Chambers, Suzanne (15) (16)
Moya, Leire (13) (14)
Clements, Judith (13) (14)
Horvath, Lisa (17) (18)
Risbridger, Gail (20) (21)
Aly, Markus (22) (23)
Pashayan, Nora (2) (24)
Cussenot, Olivier (33) (34)
Borre, Michael (35) (36)
Neal, David E. (2) (38) (39)
Hamdy, Freddie C. (39) (41)
Guo, Xin (49) (50)
Sun, Zan (50)
Giles, Graham G (52) (53)
Vega, Ana (56)
Fachal, Laura (2) (56)
Szulkin, Robert (22) (58)
Kogevinas, Manolis (59) (60) (61) (62)
Llorca, Javier (59) (63)
Castaño-Vinyals, Gemma (59) (60) (61) (62)
Stanford, Janet L (11) (66)
Nielsen, Sune F. (69) (70)
Iversen, Peter (70) (72)
Kim, Jeri (76)
John, Esther M (77) (78)
Lin, Daniel W (11) (66)
Newcomb, Lisa F (11) (66)
Cannon-Albright, Lisa (100) (101)
Ma, Jing (55)
Riboli, Elio (103)
Eeles, Rosalind A. (1) (106)

* Corresponding author

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  1. (1) Institute of Cancer Research, grid.18886.3f
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Wellcome Sanger Institute, grid.10306.34
  4. (4) Case Western Reserve University, grid.67105.35
  5. (5) University Hospitals of Cleveland, grid.241104.2
  6. (6) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  7. (7) University of Southern California, grid.42505.36
  8. (8) University of Warwick, grid.7372.1
  9. (9) University of Manchester, grid.5379.8
  10. (10) American Cancer Society, grid.422418.9
  11. (11) Fred Hutchinson Cancer Research Center, grid.270240.3
  12. (12) CHRISTUS Santa Rosa Hospital - Medical Center, 78229, San Antonio, TX, USA
  13. (13) Queensland University of Technology, grid.1024.7
  14. (14) Translational Research Institute, grid.489335.0
  15. (15) Cancer Council Queensland, grid.430282.f
  16. (16) Griffith University, grid.1022.1
  17. (17) Chris O’Brien Lifehouse, grid.419783.0
  18. (18) Garvan Institute of Medical Research, grid.415306.5
  19. (19) University of Adelaide, grid.1010.0
  20. (20) Peter MacCallum Cancer Centre, grid.1055.1
  21. (21) Monash University, grid.1002.3
  22. (22) Karolinska Institute, grid.4714.6
  23. (23) Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, Karolinska University Hospital, 171 76, Stockholm, Sweden
  24. (24) University College London, grid.83440.3b
  25. (25) Turku University Hospital, grid.410552.7
  26. (26) University of Turku, grid.1374.1
  27. (27) Department of Urology, Tampere University Hospital, University of Tampere, Kalevantie 4, FI-33014, Tampere, Finland
  28. (28) Tampere University, grid.502801.e
  29. (29) Division of Cancer Sciences, Manchester Academic Health Science Centre, Radiotherapy Related Research, Manchester NIHR Biomedical Research Centre, The Christie Hospital NHS Foundation Trust, University of Manchester, M13 9PL, Manchester, UK
  30. (30) Cambridge University Hospitals NHS Foundation Trust, grid.24029.3d
  31. (31) Harvard University, grid.38142.3c
  32. (32) Washington University in St. Louis, grid.4367.6
  33. (33) GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, F-75020, Paris, France
  34. (34) Tenon Hospital, grid.413483.9
  35. (35) Aarhus University, grid.7048.b, AU
  36. (36) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  37. (37) Oslo University Hospital, grid.55325.34
  38. (38) Cancer Research UK Cambridge Institute, grid.470869.4
  39. (39) University of Oxford, grid.4991.5
  40. (40) University of Bristol, grid.5337.2
  41. (41) Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, OX1 2JD, Oxford, UK
  42. (42) Princess Margaret Cancer Centre, grid.415224.4
  43. (43) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  44. (44) University of Rochester Medical Center, grid.412750.5
  45. (45) Albert Einstein College of Medicine, grid.251993.5
  46. (46) Queen Mary University of London, grid.4868.2
  47. (47) Second Military Medical University, grid.73113.37
  48. (48) Nanjing Medical University, grid.89957.3a
  49. (49) Chongqing Medical University, grid.203458.8
  50. (50) Liaoning Provincial People's Hospital, grid.452816.c
  51. (51) Zhongshan Hospital, grid.413087.9
  52. (52) Cancer Council Victoria, grid.3263.4
  53. (53) University of Melbourne, grid.1008.9
  54. (54) University of Tasmania, grid.1009.8
  55. (55) Brigham and Women's Hospital, grid.62560.37
  56. (56) Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, 15706, Santiago de Compostela, Spain
  57. (57) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  58. (58) Scandinavian Development Services, 182 33, Danderyd, Sweden
  59. (59) Institute of Health Carlos III, grid.413448.e
  60. (60) Center for Research in Environmental Epidemiology, grid.417617.2
  61. (61) Hospital Del Mar, grid.411142.3
  62. (62) Pompeu Fabra University, grid.5612.0
  63. (63) University of Cantabria, grid.7821.c
  64. (64) Moffitt Cancer Center, grid.468198.a
  65. (65) Louisiana State University Health Sciences Center New Orleans, grid.279863.1
  66. (66) University of Washington, grid.34477.33
  67. (67) Pomeranian Medical University, grid.107950.a
  68. (68) National Human Genome Research Institute, grid.280128.1
  69. (69) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark
  70. (70) University of Copenhagen, grid.5254.6, KU
  71. (71) Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark
  72. (72) Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, DK-2730, Herlev, Denmark
  73. (73) German Cancer Research Center, grid.7497.d
  74. (74) Krebsregister Saarland, grid.482902.5
  75. (75) University Hospital Ulm, grid.410712.1
  76. (76) The University of Texas MD Anderson Cancer Center, grid.240145.6
  77. (77) Cancer Prevention Institute of California, grid.280669.3
  78. (78) Stanford University, grid.168010.e
  79. (79) University of Porto, grid.5808.5
  80. (80) Department of Genetics, Portuguese Oncology Institute of Porto, 4200-072, Porto, Portugal
  81. (81) City Of Hope National Medical Center, grid.410425.6
  82. (82) Ghent University, grid.5342.0
  83. (83) Ghent University Hospital, grid.410566.0
  84. (84) University of Malaya, grid.10347.31
  85. (85) Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
  86. (86) University Medical Center Hamburg-Eppendorf, grid.13648.38
  87. (87) Division of Medical Oncology, Urogenital Unit, Department of Oncology at the University Hospital Centre Zagreb, Šalata 2, 10000, Zagreb, Croatia
  88. (88) University Hospital Centre Zagreb, grid.412688.1
  89. (89) Medical University of Sofia, grid.410563.5
  90. (90) University of Alberta, grid.17089.37
  91. (91) KU Leuven, grid.5596.f
  92. (92) Universitair Ziekenhuis Leuven, grid.410569.f
  93. (93) Southampton General Hospital, The University of Southampton, SO16 6YD, Southampton, UK
  94. (94) University of Surrey, grid.5475.3
  95. (95) University of California, San Diego, grid.266100.3
  96. (96) University Hospital Complex Of Vigo, grid.411855.c
  97. (97) Erasmus University Medical Center, grid.5645.2
  98. (98) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807, Villejuif Cédex, France
  99. (99) NorthShore University HealthSystem, grid.240372.0
  100. (100) George E. Wahlen Department of VA Medical Center, grid.413886.0
  101. (101) University of Utah, grid.223827.e
  102. (102) Mayo Clinic, grid.66875.3a
  103. (103) Imperial College London, grid.7445.2
  104. (104) University of Hawaii at Manoa, grid.410445.0
  105. (105) Dana-Farber Cancer Institute, grid.65499.37
  106. (106) Royal Marsden NHS Foundation Trust, grid.5072.0

Description

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

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2018: Realized

Research area: Medicine

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Research area: Medicine

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Times Cited: 35

Field Citation Ratio (FCR): 15.66

Relative Citation ratio (RCR): 2.91

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