Article open access publication

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Nature, Springer Nature, ISSN 1476-4687

Volume 514, 7520, 2014

DOI:10.1038/nature13545, Dimensions: pub.1007797493, PMC: PMC4185210, PMID: 25231870,

Authors

Perry, John R B * (1) (2) (3) (4)
Esko, Tõnu (8) (9) (10) (11)
Ang, Wei Q (13)
Corre, Tanguy (14) (15)
Porcu, Eleonora (23) (24)
Smith, Albert V. (25) (26)
Stolk, Lisette (27) (28)
Byrne, Enda M (32) (33)
Pers, Tune H. (10) (11) (35)
Andrulis, Irene L. (37) (38)
Benitez, Javier (44) (45)
Bojesen, Stig E. (47) (48)
Brauch, Hiltrud (50) (51)
Buring, Julie E (7) (8)
D'Adamo, Adamo Pio (30) (57)
Eriksson, Johan G. (16) (46) (60) (61)
de Geus, Eco E. J. (34) (68)
Giles, Graham G (69) (70)
Guénel, Pascal (71) (72)
Hall, Per (19)
Hu, Frank B (7) (8)
Hunter, David J. (7) (8) (11)
Knight, Julia A. (38) (74)
Kosma, Veli-Matti (75) (76)
Kutalik, Zoltan (14) (15)
Mannermaa, Arto (75) (76)
Melbye, Mads (17) (79)
Milne, Roger L. (69) (70)
Palotie, Aarno (11) (16) (83)
Pouta, Anneli (61) (87)
Robino, Antonietta (30) (57)
Sovio, Ulla (2) (91)
Stöckl, Doris (12) (92)
Völzke, Henry (29) (94)
Wang, Qin (2)
Loos, Ruth J F (2) (97)
McCarthy, Mark I. (4) (98) (99)
van Duijn, Cornelia M. (27) (28) (101)
Bergmann, Sven (14) (15)
Gasparini, Paolo (30) (57)
Järvelin, Marjo-Riitta (61) (87) (88) (91)
Ridker, Paul M (7) (8)
Stefansson, Kari (5) (26)
Murabito, Joanne M * (20) (55)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Exeter, grid.8391.3
  2. (2) University of Cambridge, grid.5335.0
  3. (3) King's College London, grid.13097.3c
  4. (4) Wellcome Centre for Human Genetics, grid.270683.8
  5. (5) deCODE Genetics (Iceland), grid.421812.c
  6. (6) Indiana University – Purdue University Indianapolis, grid.257413.6
  7. (7) Brigham and Women's Hospital, grid.62560.37
  8. (8) Harvard University, grid.38142.3c
  9. (9) University of Tartu, grid.10939.32
  10. (10) Boston Children's Hospital, grid.2515.3
  11. (11) Broad Institute, grid.66859.34
  12. (12) Helmholtz Zentrum München, grid.4567.0
  13. (13) University of Western Australia, grid.1012.2
  14. (14) Swiss Institute of Bioinformatics, grid.419765.8
  15. (15) University of Lausanne, grid.9851.5
  16. (16) University of Helsinki, grid.7737.4
  17. (17) State Serum Institute, grid.6203.7
  18. (18) University of North Carolina System, grid.410711.2
  19. (19) Karolinska Institute, grid.4714.6
  20. (20) Boston University, grid.189504.1
  21. (21) University of Bristol, grid.5337.2
  22. (22) University Medical Center Groningen, grid.4494.d
  23. (23) University of Sassari, grid.11450.31
  24. (24) National Research Council, grid.5326.2
  25. (25) Icelandic Heart Association, grid.420802.c
  26. (26) University of Iceland, grid.14013.37
  27. (27) Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands.
  28. (28) Erasmus University Medical Center, grid.5645.2
  29. (29) University of Greifswald, grid.5603.0
  30. (30) IRCCS Materno Infantile Burlo Garofolo, grid.418712.9
  31. (31) Washington University in St. Louis, grid.4367.6
  32. (32) University of Queensland, grid.1003.2
  33. (33) QIMR Berghofer Medical Research Institute, grid.1049.c
  34. (34) VU Amsterdam, grid.12380.38
  35. (35) Department of Systems Biology, Center for Biological Sequence Analysis, Technical 142 University of Denmark, DK-2800 Lyngby, Denmark.
  36. (36) University of Maryland, Baltimore, grid.411024.2
  37. (37) Mount Sinai Hospital, grid.416166.2
  38. (38) University of Toronto, grid.17063.33
  39. (39) University of California, Irvine, grid.266093.8
  40. (40) Sanquin, grid.417732.4
  41. (41) Azienda Sanitaria di Firenze, grid.423864.f
  42. (42) I.O.T. and Department of Medical and Surgical Critical Care, Tuscany Regional Health Agency, Florence, Italy, University of Florence, 50134 Florence, Italy.
  43. (43) Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany.
  44. (44) Centro de Investigación en Red de Enfermedades Raras (CIBERER), E-46010 Valencia, Spain.
  45. (45) Spanish National Cancer Research Centre, grid.7719.8
  46. (46) Helsinki University Central Hospital, grid.15485.3d
  47. (47) Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  48. (48) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.
  49. (49) European Institute of Oncology, grid.15667.33
  50. (50) DrMargarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany.
  51. (51) University of Tübingen, grid.10392.39
  52. (52) German Cancer Research Center, grid.7497.d
  53. (53) National Cancer Institute, grid.48336.3a
  54. (54) Mayo Clinic, grid.66875.3a
  55. (55) Boston University School of Medicine, grid.475010.7
  56. (56) University of Sheffield, grid.11835.3e
  57. (57) University of Trieste, grid.5133.4
  58. (58) University of Minnesota, grid.17635.36
  59. (59) Leiden University Medical Center, grid.10419.3d
  60. (60) Folkhälsans Forskningscentrum, grid.428673.c
  61. (61) National Institute for Health and Welfare, grid.14758.3f
  62. (62) National Institute on Aging, grid.419475.a
  63. (63) University Medical Center Hamburg-Eppendorf, grid.13648.38
  64. (64) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
  65. (65) Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.
  66. (66) National Institutes of Health, grid.94365.3d
  67. (67) Institute of Cancer Research, grid.18886.3f
  68. (68) EMGO Institute for Health and Care Research, grid.466632.3
  69. (69) Cancer Council Victoria, grid.3263.4
  70. (70) University of Melbourne, grid.1008.9
  71. (71) French Institute of Health and Medical Research, grid.7429.8
  72. (72) University of Paris-Sud, grid.5842.b
  73. (73) Southern Medical University, grid.284723.8
  74. (74) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  75. (75) Kuopio University Hospital, grid.410705.7
  76. (76) University of Eastern Finland, grid.9668.1
  77. (77) Flanders Institute for Biotechnology, grid.11486.3a
  78. (78) KU Leuven, grid.5596.f
  79. (79) Stanford University, grid.168010.e
  80. (80) Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 100, FI-00029 HUS Helsinki, Finland.
  81. (81) Department of Oncology, KULeuven (University of Leuven), Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium.
  82. (82) University of Southern Denmark, grid.10825.3e, SDU
  83. (83) Massachusetts General Hospital, grid.32224.35
  84. (84) FIRC Institute of Molecular Oncology, grid.7678.e
  85. (85) London School of Hygiene & Tropical Medicine, grid.8991.9
  86. (86) Department Pulmonary Medicine and Tuberculosis, University Groningen, University Medical Center Groningen, GRIAC Research Institute, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands.
  87. (87) Oulu University Hospital, grid.412326.0
  88. (88) University of Oulu, grid.10858.34
  89. (89) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  90. (90) Antoni van Leeuwenhoek Hospital, grid.430814.a
  91. (91) Imperial College London, grid.7445.2
  92. (92) Ludwig Maximilian University of Munich, grid.5252.0
  93. (93) University Hospital of Lausanne, grid.8515.9
  94. (94) German Centre for Cardiovascular Research, grid.452396.f
  95. (95) Department of Endocrinology, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.
  96. (96) Queensland Insitute of Medical Research, 4029, Brisbane, Queensland, Australia
  97. (97) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  98. (98) Churchill Hospital, grid.415719.f
  99. (99) University of Oxford, grid.4991.5
  100. (100) Baltimore VA Medical Center, grid.280711.d
  101. (101) Centre for Medical Systems Biology, grid.450025.6
  102. (102) University of Houston, grid.266436.3
  103. (103) Uppsala University, grid.8993.b
  104. (104) Copenhagen University Hospital, grid.4973.9, Capital Region
  105. (105) University of Copenhagen, grid.5254.6, KU
  106. (106) University College London, grid.83440.3b

Description

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

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University of Southern Denmark

University of Copenhagen

Technical University of Denmark

Danish Open Access Indicator

2014: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2014: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 332

Field Citation Ratio (FCR): 37.95

Relative Citation ratio (RCR): 10.96

Open Access Info

Green, Accepted