Article open access publication

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 10, 1, 2019

DOI:10.1038/s41467-018-08053-5, Dimensions: pub.1113473961, PMC: PMC6465407, PMID: 30988301,

Authors

Balmaña, Judith (15) (16)
Benitez, Javier (18) (19)
Blomqvist, Carl (22) (23)
Bojesen, Stig E. (26) (27) (28)
Borg, Ake (29)
Brauch, Hiltrud (10) (30) (31)
Burwinkel, Barbara (10) (33)
Campa, Daniele (10) (36)
Campbell, Ian (37) (38)
Diez, Orland (15) (16)
Fasching, Peter A. (17) (55)
Friedman, Eitan (58) (59)
Giles, Graham G. (38) (63) (64)
Hall, Per (48) (70)
He, Wei (48)
Hulick, Peter J. (73) (74)
James, Paul A. (37) (38)
Lesueur, Fabienne (91) (92) (93)
Lindström, Sara (94) (95)
Mannermaa, Arto (97) (98)
Margolin, Sara (70) (99)
Menon, Usha (102)
Olah, Edith (113)
Osorio, Ana (18) (19)
Papp, Janos (113)
Peixoto, Ana (117)
Rennert, Gad (119)
Soucy, Penny (124)
Spinelli, John J. (125) (126)
Stone, Jennifer (38) (71)
Teixeira, Manuel R. (117) (128)
Teulé, Alex (129)
Torres, Diana (10) (133)
Tung, Nadine (134)
Vega, Ana (136)
Wang, Qin (3)
Winqvist, Robert (138) (139)
Kraft, Peter (140)
Zheng, Wei (96)
Milne, Roger L. (38) (63) (64)

* Corresponding author

Affiliations

Organisations

  1. (1) QIMR Berghofer Medical Research Institute, grid.1049.c
  2. (2) Vanderbilt University, grid.152326.1
  3. (3) University of Cambridge, grid.5335.0
  4. (4) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland
  5. (5) University of Toronto, grid.17063.33
  6. (6) Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, ON, Canada
  7. (7) University of California, Irvine, grid.266093.8
  8. (8) National University Hospital of Iceland, grid.410540.4
  9. (9) University of Iceland, grid.14013.37
  10. (10) German Cancer Research Center, grid.7497.d
  11. (11) Queen's University, grid.410356.5
  12. (12) The University of Texas MD Anderson Cancer Center, grid.240145.6
  13. (13) Medical University of Vienna, grid.22937.3d
  14. (14) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  15. (15) Hospital Universitari Vall d'Hebron, grid.411083.f
  16. (16) Oncogenetics Group, Vall dHebron Institute of Oncology (VHIO), 8035, Barcelona, Spain
  17. (17) Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany
  18. (18) Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010, Valencia, Spain
  19. (19) Spanish National Cancer Research Centre, grid.7719.8
  20. (20) Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, 450054, Ufa, Russia
  21. (21) Pomeranian Medical University, grid.107950.a
  22. (22) Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland
  23. (23) Örebro University Hospital, grid.412367.5
  24. (24) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus
  25. (25) Hannover Medical School, grid.10423.34
  26. (26) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark
  27. (27) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark
  28. (28) University of Copenhagen, grid.5254.6, KU
  29. (29) Lund University, grid.4514.4
  30. (30) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  31. (31) University of Tübingen, grid.10392.39
  32. (32) Antoni van Leeuwenhoek Hospital, grid.430814.a
  33. (33) Heidelberg University, grid.7700.0
  34. (34) Hospital Clínico San Carlos, grid.411068.a
  35. (35) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  36. (36) University of Pisa, grid.5395.a
  37. (37) Peter MacCallum Cancer Centre, grid.1055.1
  38. (38) University of Melbourne, grid.1008.9
  39. (39) University of Sydney, grid.1013.3
  40. (40) American Cancer Society, grid.422418.9
  41. (41) Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain
  42. (42) University Cancer Center Hamburg, grid.412315.0
  43. (43) National Cancer Institute, grid.48336.3a
  44. (44) Columbia University, grid.21729.3f
  45. (45) Ghent University, grid.5342.0
  46. (46) Mayo Clinic, grid.66875.3a
  47. (47) University of Sheffield, grid.11835.3e
  48. (48) Karolinska Institute, grid.4714.6
  49. (49) Temple University Health System, grid.412530.1
  50. (50) Leiden University Medical Center, grid.10419.3d
  51. (51) University of Westminster, grid.12896.34
  52. (52) University of Southampton, grid.5491.9
  53. (53) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100, Copenhagen, Denmark
  54. (54) Leipzig University, grid.9647.c
  55. (55) University of California, Los Angeles, grid.19006.3e
  56. (56) Institute of Cancer Research, grid.18886.3f
  57. (57) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark
  58. (58) Tel Aviv University, grid.12136.37
  59. (59) Sheba Medical Center, grid.413795.d
  60. (60) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  61. (61) University of California, San Diego, grid.266100.3
  62. (62) Dana-Farber Cancer Institute, grid.65499.37
  63. (63) Monash University, grid.1002.3
  64. (64) Cancer Council Victoria, grid.3263.4
  65. (65) University of Kansas Medical Center, grid.412016.0
  66. (66) McGill University, grid.14709.3b
  67. (67) University of Utah, grid.223827.e
  68. (68) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94805, Villejuif, France
  69. (69) University of Southern California, grid.42505.36
  70. (70) Stockholm South General Hospital, grid.416648.9
  71. (71) University of Western Australia, grid.1012.2
  72. (72) Erasmus University Medical Center, grid.5645.2
  73. (73) NorthShore University HealthSystem, grid.240372.0
  74. (74) University of Chicago, grid.170205.1
  75. (75) Institute of Oncology NN Petrov, grid.465337.0
  76. (76) Georgetown University Medical Center, grid.411667.3
  77. (77) Macedonian Academy of Sciences and Arts, grid.419383.4
  78. (78) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  79. (79) University of Pittsburgh, grid.21925.3d
  80. (80) Stanford University, grid.168010.e
  81. (81) Memorial Sloan Kettering Cancer Center, grid.51462.34
  82. (82) Bashkir State Medical University, grid.411540.5
  83. (83) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland
  84. (84) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53177, Bonn, Germany
  85. (85) National Centre of Scientific Research Demokritos, grid.6083.d
  86. (86) Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway
  87. (87) Oslo University Hospital, grid.55325.34
  88. (88) Flanders Institute for Biotechnology, grid.11486.3a
  89. (89) KU Leuven, grid.5596.f
  90. (90) Catalan Institute of Oncology, grid.418701.b
  91. (91) Genetic Epidemiology of Cancer team, Inserm U900, 75005, Paris, France
  92. (92) Institute Curie, grid.418596.7
  93. (93) Mines ParisTech, grid.58140.38
  94. (94) Fred Hutchinson Cancer Research Center, grid.270240.3
  95. (95) University of Washington, grid.34477.33
  96. (96) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 37232, Nashville, TN, USA
  97. (97) Kuopio University Hospital, grid.410705.7
  98. (98) University of Eastern Finland, grid.9668.1
  99. (99) Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden
  100. (100) University Hospital of Heraklion, grid.412481.a
  101. (101) Ludwig Maximilian University of Munich, grid.5252.0
  102. (102) University College London, grid.83440.3b
  103. (103) Cyprus Institute of Neurology and Genetics, grid.417705.0
  104. (104) Roswell Park Cancer Institute, grid.240614.5
  105. (105) Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, 35128, Padua, Italy
  106. (106) University Health Network, grid.231844.8
  107. (107) University of Pennsylvania, grid.25879.31
  108. (108) City Of Hope National Medical Center, grid.410425.6
  109. (109) Universitair Ziekenhuis Leuven, grid.410569.f
  110. (110) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, DK-2100, Copenhagen, Denmark
  111. (111) Latvian Biomedical Research and Study Centre, grid.419210.f
  112. (112) University of California, San Francisco, grid.266102.1
  113. (113) National Institute of Oncology, grid.419617.c
  114. (114) Center for Clinical Cancer Genetics, The University of Chicago, 60637, Chicago, IL, USA
  115. (115) Aalborg Hospital, grid.27530.33, North Denmark Region
  116. (116) Aalborg University, grid.5117.2, AAU
  117. (117) Portuguese Oncology Institute, grid.418711.a
  118. (118) Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 20139, Milan, Italy
  119. (119) Technion – Israel Institute of Technology, grid.6451.6
  120. (120) Yale University, grid.47100.32
  121. (121) University Hospital of Larissa, grid.411299.6
  122. (122) King's College London, grid.13097.3c
  123. (123) University of Cologne, grid.6190.e
  124. (124) McGill University Health Centre, grid.63984.30
  125. (125) Population Oncology, BC Cancer, V5Z 1G1, Vancouver, BC, Canada
  126. (126) University of British Columbia, grid.17091.3e
  127. (127) National Institute of Environmental Health Sciences, grid.280664.e
  128. (128) University of Porto, grid.5808.5
  129. (129) Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC, 08908, Barcelona, Spain
  130. (130) Odense University Hospital, grid.7143.1, Southern Denmark Region
  131. (131) Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, 15213, Pittsburgh, PA, USA
  132. (132) The Ohio State University, grid.261331.4
  133. (133) Pontificia Universidad Javeriana, grid.41312.35
  134. (134) Beth Israel Deaconess Medical Center, grid.239395.7
  135. (135) University of Pretoria, grid.49697.35
  136. (136) Fundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain
  137. (137) Centro di Riferimento Oncologico, grid.418321.d
  138. (138) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90570, Oulu, Finland
  139. (139) University of Oulu, grid.10858.34
  140. (140) Harvard University, grid.38142.3c

Description

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

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Times Cited: 14

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