Article open access publication

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 47, 11, 2015

DOI:10.1038/ng.3412, Dimensions: pub.1026125304, PMC: PMC4661791, PMID: 26414677,

Authors

Stolk, Lisette (9) (10)
Esko, Tõnu (6) (8) (13) (15)
Altmaier, Elisabeth (18) (19) (20)
Porcu, Eleonora (27) (28) (29)
Vuckovic, Dragana (30) (34)
Yao, Jie (35)
Zhao, Wei (29)
Corre, Tanguy (36) (37)
Mangino, Massimo (39) (40)
Smith, Albert V (41) (42)
Andrulis, Irene L (44) (45)
Barbieri, Caterina (30) (33)
Benitez, Javier (50) (51)
Boerwinkle, Eric (55) (56)
Bojesen, Stig E (58) (59)
Brauch, Hiltrud (47) (62) (63)
Burwinkel, Barbara (47) (65)
Fasching, Peter A (48) (75)
Gandin, Ilaria (30) (34)
Giles, Graham G (78) (79)
Guénel, Pascal (82) (83)
Hall, Per (71)
Hu, Frank B (7) (8)
Hunter, David J (7) (8) (13)
Knight, Julia A (45) (88)
Kosma, Veli-Matti (90) (91)
Kriebel, Jennifer (18) (19) (92)
Kristensen, Vessela (60) (61) (93)
Li, Xin (8)
Mannermaa, Arto (90) (91)
Manz, Judith (18) (19)
Milne, Roger L (78) (79)
Müller-Nurasyid, Martina (20) (98) (99)
Neale, Benjamin M (13) (14)
Pirastu, Nicola N (30) (34)
Pistis, Giorgio (27) (28) (29)
Psaty, Bruce M (21) (104)
Pylkäs, Katri (105) (106)
Tomlinson, Ian (67) (112)
Truong, Thérèse (82) (83)
Wang, Qin (3)
Winqvist, Robert (105) (106)
Zheng, Wei (49)
Bergmann, Sven (36) (37)
Buring, Julie E (7) (8)
Gasparini, Paolo P (30) (34)
Gieger, Christian (18) (19) (20)
Reiner, Alex P (21) (31)
Ridker, Paul M (7) (8)
Stefansson, Kari (12) (42)
Ong, Ken K (1) (3)

* Corresponding author

Affiliations

Organisations

  1. (1) Institute of Metabolic Science, grid.470900.a
  2. (2) University of Exeter, grid.8391.3
  3. (3) University of Cambridge, grid.5335.0
  4. (4) Boston University, grid.189504.1
  5. (5) National Heart Lung and Blood Institute, grid.279885.9
  6. (6) University of Tartu, grid.10939.32
  7. (7) Brigham and Women's Hospital, grid.62560.37
  8. (8) Harvard University, grid.38142.3c
  9. (9) Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands
  10. (10) Erasmus University Medical Center, grid.5645.2
  11. (11) Massachusetts Institute of Technology, grid.116068.8
  12. (12) deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
  13. (13) Broad Institute, grid.66859.34
  14. (14) Massachusetts General Hospital, grid.32224.35
  15. (15) Boston Children's Hospital, grid.2515.3
  16. (16) University of North Carolina System, grid.410711.2
  17. (17) Indiana University – Purdue University Indianapolis, grid.257413.6
  18. (18) Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  19. (19) Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  20. (20) Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  21. (21) University of Washington, grid.34477.33
  22. (22) Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  23. (23) University of Edinburgh, grid.4305.2
  24. (24) Merck Pharmaceuticals, Boston, Massachusetts, USA
  25. (25) University of Maryland, Baltimore, grid.411024.2
  26. (26) Institute of Genetics and Biophysics, grid.419869.b
  27. (27) University of Sassari, grid.11450.31
  28. (28) National Research Council, grid.5326.2
  29. (29) University of Michigan, grid.214458.e
  30. (30) Institute for Maternal and Child Health, Scientific Institute for Research, Hospitalisation and Health Care 'Burlo Garofolo', Trieste, Italy
  31. (31) Fred Hutchinson Cancer Research Center, grid.270240.3
  32. (32) University of Greifswald, grid.5603.0
  33. (33) San Raffaele Hospital, grid.18887.3e
  34. (34) University of Trieste, grid.5133.4
  35. (35) Harbor–UCLA Medical Center, grid.239844.0
  36. (36) Swiss Institute of Bioinformatics, grid.419765.8
  37. (37) University of Lausanne, grid.9851.5
  38. (38) VU Amsterdam, grid.12380.38
  39. (39) National Institute for Health Research, grid.451056.3
  40. (40) King's College London, grid.13097.3c
  41. (41) Icelandic Heart Association, grid.420802.c
  42. (42) University of Iceland, grid.14013.37
  43. (43) National Institute on Aging, grid.419475.a
  44. (44) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  45. (45) University of Toronto, grid.17063.33
  46. (46) University of California, Irvine, grid.266093.8
  47. (47) German Cancer Research Center, grid.7497.d
  48. (48) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  49. (49) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  50. (50) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  51. (51) Spanish National Cancer Research Centre, grid.7719.8
  52. (52) City Of Hope National Medical Center, grid.410425.6
  53. (53) Mayo Clinic, grid.66875.3a
  54. (54) Helsinki University Central Hospital, grid.15485.3d
  55. (55) Baylor College of Medicine, grid.39382.33
  56. (56) The University of Texas Health Science Center at Houston, grid.267308.8
  57. (57) Hannover Medical School, grid.10423.34
  58. (58) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  59. (59) University of Copenhagen, grid.5254.6, KU
  60. (60) Oslo University Hospital, grid.55325.34
  61. (61) University of Oslo, grid.5510.1
  62. (62) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  63. (63) University of Tübingen, grid.10392.39
  64. (64) Ruhr University Bochum, grid.5570.7
  65. (65) Heidelberg University, grid.7700.0
  66. (66) National Cancer Institute, grid.48336.3a
  67. (67) Wellcome Centre for Human Genetics, grid.270683.8
  68. (68) QIMR Berghofer Medical Research Institute, grid.1049.c
  69. (69) Boston University School of Medicine, grid.475010.7
  70. (70) University of Sheffield, grid.11835.3e
  71. (71) Karolinska Institute, grid.4714.6
  72. (72) University of Minnesota, grid.17635.36
  73. (73) Leiden University Medical Center, grid.10419.3d
  74. (74) London School of Hygiene & Tropical Medicine, grid.8991.9
  75. (75) University of California, Los Angeles, grid.19006.3e
  76. (76) University Medical Center Hamburg-Eppendorf, grid.13648.38
  77. (77) Institute of Cancer Research, grid.18886.3f
  78. (78) University of Melbourne, grid.1008.9
  79. (79) Cancer Council Victoria, grid.3263.4
  80. (80) McGill University, grid.14709.3b
  81. (81) Cedars-Sinai Medical Center, grid.50956.3f
  82. (82) French Institute of Health and Medical Research, grid.7429.8
  83. (83) University of Paris-Sud, grid.5842.b
  84. (84) University of Southern California, grid.42505.36
  85. (85) University of Aberdeen, grid.7107.1
  86. (86) Shanghai Jiao Tong University, grid.16821.3c
  87. (87) Pomeranian Medical University, grid.107950.a
  88. (88) Mount Sinai Hospital, grid.416166.2
  89. (89) University of Split, grid.38603.3e
  90. (90) Kuopio University Hospital, grid.410705.7
  91. (91) University of Eastern Finland, grid.9668.1
  92. (92) German Center for Diabetes Research, grid.452622.5
  93. (93) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  94. (94) Flanders Institute for Biotechnology, grid.11486.3a
  95. (95) KU Leuven, grid.5596.f
  96. (96) Wake Forest University, grid.241167.7
  97. (97) Technical University of Munich, grid.6936.a
  98. (98) German Centre for Cardiovascular Research, grid.452396.f
  99. (99) Ludwig Maximilian University of Munich, grid.5252.0
  100. (100) Universitair Ziekenhuis Leuven, grid.410569.f
  101. (101) University of Pittsburgh, grid.21925.3d
  102. (102) University of Glasgow, grid.8756.c
  103. (103) FIRC Institute of Molecular Oncology, grid.7678.e
  104. (104) Group Health Cooperative, grid.280243.f
  105. (105) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  106. (106) University of Oulu, grid.10858.34
  107. (107) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  108. (108) Antoni van Leeuwenhoek Hospital, grid.430814.a
  109. (109) University Hospital Cologne, grid.411097.a
  110. (110) Laval University, grid.23856.3a
  111. (111) The Ohio State University, grid.261331.4
  112. (112) Churchill Hospital, grid.415719.f
  113. (113) Icelandic Cancer Registry, Reykjavik, Iceland
  114. (114) Vanderbilt University Medical Center, grid.412807.8
  115. (115) Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  116. (116) LifeLines Cohort Study and Biobank, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  117. (117) National Centre of Scientific Research Demokritos, grid.6083.d
  118. (118) University Medical Center Groningen, grid.4494.d

Description

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

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NORA University Profiles

University of Copenhagen

Danish Open Access Indicator

2015: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2015: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 158

Field Citation Ratio (FCR): 26.98

Relative Citation ratio (RCR): 5.8

Open Access Info

Green, Accepted