Preprint open access publication

Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

bioRxiv, Cold Spring Harbor Laboratory,

2016

DOI:10.1101/076794, Dimensions: pub.1085114084,

Authors

Loh, Po-Ru (5) (9)
Mangino, Massimo (23) (24)
Smith, Albert V. (2) (33)
Andrulis, Irene L. (36) (37)
Benitez, Javier (40) (41)
Bergmann, Sven (42) (43)
Bojesen, Stig E. (46) (47) (48)
Brauch, Hiltrud (49) (50) (51)
Buring, Julie E (4) (5)
Corre, Tanguy (42) (43) (44)
Cousminer, Diana L (56) (57)
Fasching, Peter A. (39) (61)
Giles, Graham G (66) (67)
Grallert, Harald (11) (12) (68)
Hall, Per (20)
Hu, Frank (4) (5)
Hunter, David (4) (5)
Järvelin, Marjo-Riitta (72) (73) (74) (75)
Kutalik, Zoltan (42) (44)
Mannermaa, Arto (80) (81)
McCarthy, Mark I. (82) (83) (84)
Meisinger, Christa (11) (85)
Milne, Roger L. (66) (67)
Mulligan, Anna M. (37) (89)
Palotie, Aarno (9) (60) (92) (93)
Peters, Annette (11) (68)
Rueedi, Rico (42) (43)
Sovio, Ulla (1) (74)
Stampfer, Meir (4) (5)
Wang, Qin (1)
Winqvist, Robert (75) (98)
Cucca, Francesco (31) (100)
Esko, Tõnu (9) (30)
Gieger, Christian (11) (12) (68)
Price, Alkes L (5) (6) (9)
Ridker, Paul M (4) (5)
Stöckl, Doris (11) (96)
Chang-Claude, Jenny (51) (104)
Hinds, David (103)
Murabito, Joanne M (22) (105)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) University of Iceland, grid.14013.37
  3. (3) CODE genetics/Amgen, Inc., IS-101 Reykjavik, Iceland
  4. (4) Brigham and Women's Hospital, grid.62560.37
  5. (5) Harvard University, grid.38142.3c
  6. (6) Massachusetts Institute of Technology, grid.116068.8
  7. (7) University of Exeter, grid.8391.3
  8. (8) Gladstone Institutes, grid.249878.8
  9. (9) Broad Institute, grid.66859.34
  10. (10) Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, 85764 Neuherberg, Germany
  11. (11) Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, 85764 Neuherberg, Germany
  12. (12) Research Unit of Molecular Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, 85764 Neuherberg, Germany
  13. (13) University Medical Center Groningen, grid.4494.d
  14. (14) Vita-Salute San Raffaele University, grid.15496.3f
  15. (15) University of Edinburgh, grid.4305.2
  16. (16) Division of Epidemiology & Community Health, University of Minnesotta, Minneapolis MN 55455
  17. (17) Vanderbilt University, grid.152326.1
  18. (18) Indiana University – Purdue University Indianapolis, grid.257413.6
  19. (19) VU Amsterdam, grid.12380.38
  20. (20) Karolinska Institute, grid.4714.6
  21. (21) University of Split, grid.38603.3e
  22. (22) Boston University, grid.189504.1
  23. (23) National Institute for Health Research, grid.451056.3
  24. (24) King's College London, grid.13097.3c
  25. (25) University of Trieste, grid.5133.4
  26. (26) University of Bristol, grid.5337.2
  27. (27) QIMR Berghofer Medical Research Institute, grid.1049.c
  28. (28) Leiden University Medical Center, grid.10419.3d
  29. (29) Institute of Genetics and Biophysics – CNR, via Pietro Castellino 111, 80131, Naples, Italy
  30. (30) University of Tartu, grid.10939.32
  31. (31) National Research Council, grid.5326.2
  32. (32) Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, EH16 4TJ, Scotland
  33. (33) Icelandic Heart Association, grid.420802.c
  34. (34) Erasmus University Medical Center, grid.5645.2
  35. (35) University of Greifswald, grid.5603.0
  36. (36) Mount Sinai Hospital, grid.416166.2
  37. (37) University of Toronto, grid.17063.33
  38. (38) Azienda Sanitaria di Firenze, grid.423864.f
  39. (39) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  40. (40) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  41. (41) Spanish National Cancer Research Centre, grid.7719.8
  42. (42) Swiss Institute of Bioinformatics, grid.419765.8
  43. (43) University of Lausanne, grid.9851.5
  44. (44) Institute of Social and Preventive Medicine, grid.482968.9
  45. (45) The University of Texas Health Science Center at Houston, grid.267308.8
  46. (46) Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  47. (47) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  48. (48) University of Copenhagen, grid.5254.6, KU
  49. (49) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  50. (50) University of Tübingen, grid.10392.39
  51. (51) German Cancer Research Center, grid.7497.d
  52. (52) Ruhr University Bochum, grid.5570.7
  53. (53) IRCCS Materno Infantile Burlo Garofolo, grid.418712.9
  54. (54) National Cancer Institute, grid.48336.3a
  55. (55) Mayo Clinic, grid.66875.3a
  56. (56) Children's Hospital of Philadelphia, grid.239552.a
  57. (57) University of Pennsylvania, grid.25879.31
  58. (58) University of Sheffield, grid.11835.3e
  59. (59) London School of Hygiene & Tropical Medicine, grid.8991.9
  60. (60) University of Helsinki, grid.7737.4
  61. (61) University of California, Los Angeles, grid.19006.3e
  62. (62) University of North Carolina at Chapel Hill, grid.10698.36
  63. (63) National Institute on Aging, grid.419475.a
  64. (64) University Medical Center Hamburg-Eppendorf, grid.13648.38
  65. (65) Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  66. (66) Cancer Council Victoria, grid.3263.4
  67. (67) University of Melbourne, grid.1008.9
  68. (68) German Center for Diabetes Research, grid.452622.5
  69. (69) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  70. (70) National Institutes of Health, grid.94365.3d
  71. (71) Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
  72. (72) Oulu University Hospital, grid.412326.0
  73. (73) National Institute for Health and Welfare, grid.14758.3f
  74. (74) Imperial College London, grid.7445.2
  75. (75) University of Oulu, grid.10858.34
  76. (76) Flanders Institute for Biotechnology, grid.11486.3a
  77. (77) KU Leuven, grid.5596.f
  78. (78) University of Washington, grid.34477.33
  79. (79) Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine
  80. (80) Kuopio University Hospital, grid.410705.7
  81. (81) University of Eastern Finland, grid.9668.1
  82. (82) Churchill Hospital, grid.415719.f
  83. (83) University of Oxford, grid.4991.5
  84. (84) Wellcome Centre for Human Genetics, grid.270683.8
  85. (85) University Hospital Augsburg, grid.419801.5
  86. (86) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  87. (87) Cyprus Institute of Neurology and Genetics, grid.417705.0
  88. (88) University of Queensland, grid.1003.2
  89. (89) University Health Network, grid.231844.8
  90. (90) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  91. (91) Queensland University of Technology, grid.1024.7
  92. (92) Massachusetts General Hospital, grid.32224.35
  93. (93) Wellcome Sanger Institute, grid.10306.34
  94. (94) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  95. (95) Antoni van Leeuwenhoek Hospital, grid.430814.a
  96. (96) Ludwig Maximilian University of Munich, grid.5252.0
  97. (97) University Hospital of Lausanne, grid.8515.9
  98. (98) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  99. (99) Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  100. (100) University of Sassari, grid.11450.31
  101. (101) University of Southern Denmark, grid.10825.3e, SDU
  102. (102) University of California, San Francisco, grid.266102.1
  103. (103) Me Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA
  104. (104) University Cancer Center Hamburg, grid.412315.0
  105. (105) Boston University School of Medicine, grid.475010.7

Description

Abstract The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5×10 −8 ) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

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Times Cited: 2

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Green, Published