Article open access publication

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 49, 6, 2017

DOI:10.1038/ng.3841, Dimensions: pub.1085051707, PMC: PMC5841952, PMID: 28436984,

Authors

Loh, Po-Ru (6) (10)
Mangino, Massimo (24) (25)
Smith, Albert V (3) (34)
Andrulis, Irene L (37) (38)
Benitez, Javier (41) (42)
Bergmann, Sven (43) (44)
Bojesen, Stig E (47) (48) (49)
Brauch, Hiltrud (50) (51) (52)
Buring, Julie E (5) (6)
Corre, Tanguy (43) (44) (45)
Cousminer, Diana L (57) (58)
Fasching, Peter A (40) (62)
Giles, Graham G (67) (68)
Grallert, Harald (12) (13) (69)
Hall, Per (21)
Hu, Frank (5) (6)
Hunter, David J (5) (6)
Järvelin, Marjo-Riitta (73) (74) (75) (76)
Kellis, Manolis (7) (10)
Kutalik, Zoltan (43) (45)
Mannermaa, Arto (81) (82)
McCarthy, Mark I (83) (84) (85)
Meisinger, Christa (12) (86)
Milne, Roger L (67) (68)
Mulligan, Anna M (38) (90)
Palotie, Aarno (10) (61) (94) (95)
Peters, Annette (12) (69)
Rueedi, Rico (43) (44)
Sovio, Ulla (2) (75)
Stampfer, Meir (5) (6)
Wang, Qin (2)
Winqvist, Robert (76) (100)
Cucca, Francesco (32) (102)
Esko, Tõnu (10) (31)
Gieger, Christian (12) (13) (69)
Price, Alkes L (6) (7) (10)
Ridker, Paul M (5) (6)
Stöckl, Doris (12) (98)
Chang-Claude, Jenny (52) (106)
Hinds, David (105)
Murabito, Joanne M (23) (107)
Ong, Ken K * (1) (2)

* Corresponding author

Affiliations

Organisations

  1. (1) Institute of Metabolic Science, grid.470900.a
  2. (2) University of Cambridge, grid.5335.0
  3. (3) University of Iceland, grid.14013.37
  4. (4) deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
  5. (5) Brigham and Women's Hospital, grid.62560.37
  6. (6) Harvard University, grid.38142.3c
  7. (7) Massachusetts Institute of Technology, grid.116068.8
  8. (8) University of Exeter, grid.8391.3
  9. (9) Gladstone Institutes, grid.249878.8
  10. (10) Broad Institute, grid.66859.34
  11. (11) Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  12. (12) Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  13. (13) Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
  14. (14) University Medical Center Groningen, grid.4494.d
  15. (15) Vita-Salute San Raffaele University, grid.15496.3f
  16. (16) University of Edinburgh, grid.4305.2
  17. (17) University of Minnesota, grid.17635.36
  18. (18) Vanderbilt University, grid.152326.1
  19. (19) Indiana University – Purdue University Indianapolis, grid.257413.6
  20. (20) VU Amsterdam, grid.12380.38
  21. (21) Karolinska Institute, grid.4714.6
  22. (22) University of Split, grid.38603.3e
  23. (23) Boston University, grid.189504.1
  24. (24) National Institute for Health Research, grid.451056.3
  25. (25) King's College London, grid.13097.3c
  26. (26) University of Trieste, grid.5133.4
  27. (27) University of Bristol, grid.5337.2
  28. (28) QIMR Berghofer Medical Research Institute, grid.1049.c
  29. (29) Leiden University Medical Center, grid.10419.3d
  30. (30) Institute of Genetics and Biophysics, grid.419869.b
  31. (31) University of Tartu, grid.10939.32
  32. (32) National Research Council, grid.5326.2
  33. (33) Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
  34. (34) Icelandic Heart Association, grid.420802.c
  35. (35) Erasmus University Medical Center, grid.5645.2
  36. (36) University of Greifswald, grid.5603.0
  37. (37) Mount Sinai Hospital, grid.416166.2
  38. (38) University of Toronto, grid.17063.33
  39. (39) Azienda Sanitaria di Firenze, grid.423864.f
  40. (40) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  41. (41) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  42. (42) Spanish National Cancer Research Centre, grid.7719.8
  43. (43) Swiss Institute of Bioinformatics, grid.419765.8
  44. (44) University of Lausanne, grid.9851.5
  45. (45) Institute of Social and Preventive Medicine, grid.482968.9
  46. (46) The University of Texas Health Science Center at Houston, grid.267308.8
  47. (47) Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  48. (48) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  49. (49) University of Copenhagen, grid.5254.6, KU
  50. (50) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  51. (51) University of Tübingen, grid.10392.39
  52. (52) German Cancer Research Center, grid.7497.d
  53. (53) Ruhr University Bochum, grid.5570.7
  54. (54) IRCCS Materno Infantile Burlo Garofolo, grid.418712.9
  55. (55) National Cancer Institute, grid.48336.3a
  56. (56) Mayo Clinic, grid.66875.3a
  57. (57) Children's Hospital of Philadelphia, grid.239552.a
  58. (58) University of Pennsylvania, grid.25879.31
  59. (59) University of Sheffield, grid.11835.3e
  60. (60) London School of Hygiene & Tropical Medicine, grid.8991.9
  61. (61) University of Helsinki, grid.7737.4
  62. (62) University of California, Los Angeles, grid.19006.3e
  63. (63) University of North Carolina at Chapel Hill, grid.10698.36
  64. (64) National Institute on Aging, grid.419475.a
  65. (65) University Medical Center Hamburg-Eppendorf, grid.13648.38
  66. (66) Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  67. (67) Cancer Council Victoria, grid.3263.4
  68. (68) University of Melbourne, grid.1008.9
  69. (69) German Center for Diabetes Research, grid.452622.5
  70. (70) Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  71. (71) National Institutes of Health, grid.94365.3d
  72. (72) Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois, USA
  73. (73) Oulu University Hospital, grid.412326.0
  74. (74) National Institute for Health and Welfare, grid.14758.3f
  75. (75) Imperial College London, grid.7445.2
  76. (76) University of Oulu, grid.10858.34
  77. (77) Flanders Institute for Biotechnology, grid.11486.3a
  78. (78) KU Leuven, grid.5596.f
  79. (79) University of Washington, grid.34477.33
  80. (80) Wake Forest University, grid.241167.7
  81. (81) Kuopio University Hospital, grid.410705.7
  82. (82) University of Eastern Finland, grid.9668.1
  83. (83) Churchill Hospital, grid.415719.f
  84. (84) University of Oxford, grid.4991.5
  85. (85) Wellcome Centre for Human Genetics, grid.270683.8
  86. (86) University Hospital Augsburg, grid.419801.5
  87. (87) Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
  88. (88) Cyprus Institute of Neurology and Genetics, grid.417705.0
  89. (89) University of Queensland, grid.1003.2
  90. (90) University Health Network, grid.231844.8
  91. (91) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  92. (92) Queensland University of Technology, grid.1024.7
  93. (93) University of Glasgow, grid.8756.c
  94. (94) Massachusetts General Hospital, grid.32224.35
  95. (95) Wellcome Sanger Institute, grid.10306.34
  96. (96) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  97. (97) Antoni van Leeuwenhoek Hospital, grid.430814.a
  98. (98) Ludwig Maximilian University of Munich, grid.5252.0
  99. (99) University Hospital of Lausanne, grid.8515.9
  100. (100) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  101. (101) Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  102. (102) University of Sassari, grid.11450.31
  103. (103) University of Southern Denmark, grid.10825.3e, SDU
  104. (104) University of California, San Francisco, grid.266102.1
  105. (105) 23andMe (United States), grid.420283.f
  106. (106) University Cancer Center Hamburg, grid.412315.0
  107. (107) Boston University School of Medicine, grid.475010.7

Description

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

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University of Copenhagen

University of Southern Denmark

Danish Open Access Indicator

2017: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2017: Level 2

Research area: Medicine

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Times Cited: 182

Field Citation Ratio (FCR): 53.36

Relative Citation ratio (RCR): 11.27

Open Access Info

Green, Accepted