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

doi:10.1038/ng.3841

. 2017 Jun;49(6):834-841.

doi: 10.1038/ng.3841. Epub 2017 Apr 24.

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

Felix R Day¹, Deborah J Thompson², Hannes Helgason^{3

4}, Daniel I Chasman^{5

6}, Hilary Finucane^{7

8}, Patrick Sulem³, Katherine S Ruth⁹, Sean Whalen¹⁰, Abhishek K Sarkar^{11

12}, Eva Albrecht¹³, Elisabeth Altmaier^{14

15}, Marzyeh Amini¹⁶, Caterina M Barbieri¹⁷, Thibaud Boutin¹⁸, Archie Campbell¹⁹, Ellen Demerath²⁰, Ayush Giri^{21

22}, Chunyan He^{23

24}, Jouke J Hottenga²⁵, Robert Karlsson²⁶, Ivana Kolcic²⁷, Po-Ru Loh^{7

28}, Kathryn L Lunetta^{29

30}, Massimo Mangino^{31

32}, Brumat Marco³³, George McMahon³⁴, Sarah E Medland³⁵, Ilja M Nolte¹⁶, Raymond Noordam³⁶, Teresa Nutile³⁷, Lavinia Paternoster^{34

38}, Natalia Perjakova³⁹, Eleonora Porcu⁴⁰, Lynda M Rose⁵, Katharina E Schraut^{41

42}, Ayellet V Segrè⁴³, Albert V Smith^{44

45}, Lisette Stolk⁴⁶, Alexander Teumer⁴⁷, Irene L Andrulis^{48

49}, Stefania Bandinelli⁵⁰, Matthias W Beckmann⁵¹, Javier Benitez^{52

53}, Sven Bergmann^{54

55}, Murielle Bochud⁵⁶, Eric Boerwinkle⁵⁷, Stig E Bojesen^{58

59

60}, Manjeet K Bolla², Judith S Brand²⁶, Hiltrud Brauch^{61

62

63}, Hermann Brenner^{63

64

65}, Linda Broer⁴⁶, Thomas Brüning⁶⁶, Julie E Buring^{5

6}, Harry Campbell⁴², Eulalia Catamo⁶⁷, Stephen Chanock⁶⁸, Georgia Chenevix-Trench⁶⁹, Tanguy Corre^{54

55

56}, Fergus J Couch⁷⁰, Diana L Cousminer^{71

72}, Angela Cox⁷³, Laura Crisponi⁴⁰, Kamila Czene²⁶, George Davey Smith^{34

38}, Eco J C N de Geus²⁵, Renée de Mutsert⁷⁴, Immaculata De Vivo^{7

75}, Joe Dennis², Peter Devilee^{76

77}, Isabel Dos-Santos-Silva⁷⁸, Alison M Dunning⁷⁹, Johan G Eriksson⁸⁰, Peter A Fasching^{51

81}, Lindsay Fernández-Rhodes⁸², Luigi Ferrucci⁸³, Dieter Flesch-Janys^{84

85}, Lude Franke⁸⁶, Marike Gabrielson²⁶, Ilaria Gandin³³, Graham G Giles^{87

88}, Harald Grallert^{14

15

89}, Daniel F Gudbjartsson^{3

4}, Pascal Guénel⁹⁰, Per Hall²⁶, Emily Hallberg⁹¹, Ute Hamann⁹², Tamara B Harris⁹³, Catharina A Hartman⁹⁴, Gerardo Heiss⁸², Maartje J Hooning⁹⁵, John L Hopper⁸⁸, Frank Hu^{75

96}, David J Hunter^{7

75

96}, M Arfan Ikram⁹⁷, Hae Kyung Im⁹⁸, Marjo-Riitta Järvelin^{99

100

101

102

103}, Peter K Joshi⁴², David Karasik^{6

104}, Manolis Kellis^{11

12}, Zoltan Kutalik^{54

56}, Genevieve LaChance³¹, Diether Lambrechts^{105

106}, Claudia Langenberg¹, Lenore J Launer⁹³, Joop S E Laven¹⁰⁷, Stefania Lenarduzzi⁶⁷, Jingmei Li²⁶, Penelope A Lind³⁵, Sara Lindstrom¹⁰⁸, YongMei Liu¹⁰⁹, Jian'an Luan¹, Reedik Mägi³⁹, Arto Mannermaa^{110

111

112}, Hamdi Mbarek²⁵, Mark I McCarthy^{113

114

115}, Christa Meisinger^{14

116}, Thomas Meitinger¹¹⁷, Cristina Menni³¹, Andres Metspalu³⁹, Kyriaki Michailidou^{2

118}, Lili Milani³⁹, Roger L Milne^{87

88}, Grant W Montgomery¹¹⁹, Anna M Mulligan^{120

121}, Mike A Nalls¹²², Pau Navarro¹⁸, Heli Nevanlinna¹²³, Dale R Nyholt¹²⁴, Albertine J Oldehinkel¹²⁵, Tracy A O'Mara⁶⁹, Sandosh Padmanabhan¹²⁶, Aarno Palotie^{28

127

128

129

130

131}, Nancy Pedersen²⁶, Annette Peters^{14

89}, Julian Peto⁷⁸, Paul D P Pharoah^{2

79}, Anneli Pouta¹³², Paolo Radice¹³³, Iffat Rahman¹³⁴, Susan M Ring^{34

38}, Antonietta Robino⁶⁷, Frits R Rosendaal⁷⁴, Igor Rudan⁴², Rico Rueedi^{54

55}, Daniela Ruggiero³⁷, Cinzia F Sala¹⁷, Marjanka K Schmidt^{135

136}, Robert A Scott¹, Mitul Shah⁷⁹, Rossella Sorice³⁷, Melissa C Southey¹³⁷, Ulla Sovio^{99

138}, Meir Stampfer^{7

75}, Maristella Steri⁴⁰, Konstantin Strauch^{13

139}, Toshiko Tanaka⁸³, Emmi Tikkanen^{131

140}, Nicholas J Timpson^{34

38}, Michela Traglia¹⁷, Thérèse Truong⁹⁰, Jonathan P Tyrer⁷⁹, André G Uitterlinden^{46

97}, Digna R Velez Edwards^{22

141

142}, Veronique Vitart¹⁸, Uwe Völker¹⁴³, Peter Vollenweider¹⁴⁴, Qin Wang², Elisabeth Widen¹³¹, Ko Willems van Dijk^{77

145

146}, Gonneke Willemsen²⁵, Robert Winqvist^{147

148}, Bruce H R Wolffenbuttel¹⁴⁹, Jing Hua Zhao¹, Magdalena Zoledziewska⁴⁰, Marek Zygmunt¹⁵⁰, Behrooz Z Alizadeh¹⁶, Dorret I Boomsma²⁵, Marina Ciullo³⁷, Francesco Cucca^{40

151}, Tõnu Esko^{28

39}, Nora Franceschini⁸², Christian Gieger^{14

15

89}, Vilmundur Gudnason^{44

45}, Caroline Hayward¹⁸, Peter Kraft^{7

152}, Debbie A Lawlor^{34

38}, Patrik K E Magnusson²⁶, Nicholas G Martin³⁵, Dennis O Mook-Kanamori^{74

153}, Ellen A Nohr¹⁵⁴, Ozren Polasek²⁷, David Porteous¹⁹, Alkes L Price^{7

8

28}, Paul M Ridker^{5

6}, Harold Snieder¹⁶, Tim D Spector³¹, Doris Stöckl^{14

155}, Daniela Toniolo¹⁷, Sheila Ulivi⁶⁷, Jenny A Visser⁴⁶, Henry Völzke⁴⁷, Nicholas J Wareham¹, James F Wilson^{18

42}; LifeLines Cohort Study; InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL consortium; Amanda B Spurdle⁶⁹, Unnur Thorsteindottir^{3

44}, Katherine S Pollard^{10

156}, Douglas F Easton^{2

79}, Joyce Y Tung¹⁵⁷, Jenny Chang-Claude^{158

159}, David Hinds¹⁵⁷, Anna Murray⁹, Joanne M Murabito^{30

160}, Kari Stefansson^{3

44}, Ken K Ong^{1

161}, John R B Perry¹

Affiliations

¹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
⁴ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁶ Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
⁸ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁹ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
¹⁰ Gladstone Institutes, San Francisco, California, USA.
¹¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹³ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷ Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
¹⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁹ Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
²¹ Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
²² Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
²³ Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, USA.
²⁴ Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, USA.
²⁵ Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁷ Faculty of Medicine, University of Split, Split, Croatia.
²⁸ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
³⁰ NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.
³¹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
³² National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
³³ Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Trieste, Italy.
³⁴ School of Social and Community Medicine, University of Bristol, Bristol, UK.
³⁵ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁶ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
³⁷ Institute of Genetics and Biophysics, CNR, Naples, Italy.
³⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁴⁰ Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
⁴¹ Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.
⁴² Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁴³ Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.
⁴⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁵ Icelandic Heart Association, Kopavogur, Iceland.
⁴⁶ Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
⁴⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴⁹ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁵⁰ Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
⁵¹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
⁵² Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
⁵⁴ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵⁵ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵⁶ Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
⁵⁷ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵⁸ Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁵⁹ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁰ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶¹ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶² University of Tübingen, Tübingen, Germany.
⁶³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁶⁶ Institute for Prevention and Occupational Medicine of German Social Accident Insurance, Institute of Ruhr University Bochum (IPA), Bochum, Germany.
⁶⁷ Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
⁶⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁶⁹ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁷¹ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁷² Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷³ Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
⁷⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁸ Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
⁷⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁸⁰ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁸¹ David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angles, California, USA.
⁸² Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA.
⁸³ Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.
⁸⁴ Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
⁸⁵ Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
⁸⁶ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
⁸⁷ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁸⁸ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁸⁹ German Center for Diabetes Research, Neuherberg, Germany.
⁹⁰ Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁹¹ Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
⁹² Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
⁹³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.
⁹⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹⁵ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁹⁶ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
⁹⁷ Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
⁹⁸ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
⁹⁹ Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
¹⁰⁰ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁰¹ Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
¹⁰² Institute of Health Sciences, University of Oulu, Oulu, Finland.
¹⁰³ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
¹⁰⁴ Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts, USA.
¹⁰⁵ Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
¹⁰⁶ Vesalius Research Center (VRC), VIB, Leuven, Belgium.
¹⁰⁷ Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, the Netherlands.
¹⁰⁸ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁰⁹ Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
¹¹⁰ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
¹¹¹ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹¹² Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
¹¹³ NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
¹¹⁴ Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
¹¹⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹¹⁶ Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany.
¹¹⁷ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹⁸ Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹⁹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹²⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹²¹ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
¹²² Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
¹²³ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹²⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
¹²⁵ Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁶ British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹²⁷ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹²⁹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
¹³⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹³¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹³² National Institute for Health and Welfare, Helsinki, Finland.
¹³³ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹³⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³⁵ Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹³⁶ Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹³⁷ Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
¹³⁸ Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
¹³⁹ Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁴⁰ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁴¹ Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
¹⁴² Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹⁴³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁴⁴ University Hospital of Lausanne, Lausanne, Switzerland.
¹⁴⁵ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁴⁶ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
¹⁴⁷ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁴⁸ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
¹⁴⁹ Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
¹⁵⁰ Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany.
¹⁵¹ Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
¹⁵² Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
¹⁵³ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
¹⁵⁴ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁵⁵ Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig Maximilians University, Munich, Germany.
¹⁵⁶ Division of Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, California, USA.
¹⁵⁷ 23andMe, Inc., Mountain View, California, USA.
¹⁵⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵⁹ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶⁰ Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts, USA.
¹⁶¹ Department of Paediatrics, University of Cambridge, Cambridge, UK.

PMID: 28436984
PMCID: PMC5841952
DOI: 10.1038/ng.3841

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

Felix R Day et al. Nat Genet. 2017 Jun.

. 2017 Jun;49(6):834-841.

doi: 10.1038/ng.3841. Epub 2017 Apr 24.

Authors

Affiliations

¹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
⁴ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁶ Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
⁸ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁹ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
¹⁰ Gladstone Institutes, San Francisco, California, USA.
¹¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹³ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷ Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
¹⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁹ Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
²¹ Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
²² Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
²³ Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, USA.
²⁴ Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, USA.
²⁵ Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁷ Faculty of Medicine, University of Split, Split, Croatia.
²⁸ Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
³⁰ NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.
³¹ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
³² National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
³³ Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Trieste, Italy.
³⁴ School of Social and Community Medicine, University of Bristol, Bristol, UK.
³⁵ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁶ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
³⁷ Institute of Genetics and Biophysics, CNR, Naples, Italy.
³⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁴⁰ Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
⁴¹ Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.
⁴² Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁴³ Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.
⁴⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴⁵ Icelandic Heart Association, Kopavogur, Iceland.
⁴⁶ Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
⁴⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴⁹ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁵⁰ Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
⁵¹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
⁵² Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
⁵⁴ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵⁵ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵⁶ Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
⁵⁷ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵⁸ Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁵⁹ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁰ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶¹ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶² University of Tübingen, Tübingen, Germany.
⁶³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁶⁶ Institute for Prevention and Occupational Medicine of German Social Accident Insurance, Institute of Ruhr University Bochum (IPA), Bochum, Germany.
⁶⁷ Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
⁶⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁶⁹ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁷¹ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁷² Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷³ Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
⁷⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁸ Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
⁷⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁸⁰ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁸¹ David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angles, California, USA.
⁸² Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA.
⁸³ Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.
⁸⁴ Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
⁸⁵ Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
⁸⁶ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
⁸⁷ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁸⁸ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁸⁹ German Center for Diabetes Research, Neuherberg, Germany.
⁹⁰ Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁹¹ Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
⁹² Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
⁹³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.
⁹⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹⁵ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁹⁶ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
⁹⁷ Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
⁹⁸ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
⁹⁹ Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
¹⁰⁰ Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁰¹ Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
¹⁰² Institute of Health Sciences, University of Oulu, Oulu, Finland.
¹⁰³ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
¹⁰⁴ Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts, USA.
¹⁰⁵ Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
¹⁰⁶ Vesalius Research Center (VRC), VIB, Leuven, Belgium.
¹⁰⁷ Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, the Netherlands.
¹⁰⁸ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁰⁹ Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
¹¹⁰ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
¹¹¹ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹¹² Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
¹¹³ NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
¹¹⁴ Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
¹¹⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹¹⁶ Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany.
¹¹⁷ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹⁸ Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹⁹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹²⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹²¹ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
¹²² Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
¹²³ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹²⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
¹²⁵ Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹²⁶ British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹²⁷ Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹²⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹²⁹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
¹³⁰ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹³¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹³² National Institute for Health and Welfare, Helsinki, Finland.
¹³³ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹³⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³⁵ Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹³⁶ Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹³⁷ Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
¹³⁸ Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
¹³⁹ Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁴⁰ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁴¹ Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
¹⁴² Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹⁴³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁴⁴ University Hospital of Lausanne, Lausanne, Switzerland.
¹⁴⁵ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁴⁶ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
¹⁴⁷ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
¹⁴⁸ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
¹⁴⁹ Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
¹⁵⁰ Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany.
¹⁵¹ Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
¹⁵² Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
¹⁵³ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
¹⁵⁴ Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁵⁵ Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig Maximilians University, Munich, Germany.
¹⁵⁶ Division of Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, California, USA.
¹⁵⁷ 23andMe, Inc., Mountain View, California, USA.
¹⁵⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵⁹ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶⁰ Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts, USA.
¹⁶¹ Department of Paediatrics, University of Cambridge, Cambridge, UK.

PMID: 28436984
PMCID: PMC5841952
DOI: 10.1038/ng.3841

Abstract

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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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

**Figure 1**
GTEx tissue enrichment using LD score regression. Numbers on the x axis correspond to sample number for each tissue. The dashed line represents significance at FDR < 5%, and the solid horizontal line represents Bonferroni-corrected significance for the number of tissues tested.

**Figure 2**
Stronger effects of AAM-associated signals on early menarche than late menarche in women. The 377 index AAM-associated SNPs are ordered from smallest to largest P value for their continuous association with AAM. The y axis shows the log-transformed odds ratio for each SNP on early menarche (blue; ages 8–11 years, inclusive) or late menarche (red; ages 15–19 years, inclusive). The reference group comprises women with menarche at 13 years. Insert, −log₁₀ P values for heterogeneity (based on Cochran’s Q) between the associations for early and late menarche plotted against the −log₁₀ P value for the continuous AAM association.

**Figure 3**
Effects and 95% confidence intervals of genetically predicted AAM on risks for various sex-steroid-sensitive cancers, adjusted for the effects of the same AAM variants on BMI. AAM was predicted by all 375 autosomal AAM-associated SNPs, and models were adjusted for the genetic effects of the same AAM variants on BMI. Three further genetic score associations are shown as sensitivity analyses for each outcome: first, AAM predicted by the 314 AAM-associated SNPs that were not also associated with BMI in the BCAC iCOGS sample (at a nominal level of P < 0.05); second, AAM predicted by the 61 AAM-associated SNPs that were also associated with BMI in this sample; and, third, AAM predicted by all 375 autosomal AAM-associated SNPs (unadjusted for BMI).

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Comment in

Reproductive endocrinology: Puberty timing and cancer risk.
Holmes D. Holmes D. Nat Rev Endocrinol. 2017 Jul;13(7):377. doi: 10.1038/nrendo.2017.63. Epub 2017 May 12. Nat Rev Endocrinol. 2017. PMID: 28497815 No abstract available.

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References

1. Parent AS, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 2003;24:668–693. - PubMed
1. Perry JR, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat. Rev. Endocrinol. 2015;11:725–734. - PMC - PubMed
1. Perry JR, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514:92–97. - PMC - PubMed
1. Lunetta KL, et al. Rare coding variants and X-linked loci associated with age at menarche. Nat. Commun. 2015;6:7756. - PMC - PubMed
1. Day FR, et al. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat. Commun. 2015;6:8842. - PMC - PubMed

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[1] Parent AS, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 2003;24:668–693. - PubMed

[2] Parent AS, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 2003;24:668–693. - PubMed

[3] Perry JR, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat. Rev. Endocrinol. 2015;11:725–734. - PMC - PubMed

[4] Perry JR, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat. Rev. Endocrinol. 2015;11:725–734. - PMC - PubMed

[5] Perry JR, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514:92–97. - PMC - PubMed

[6] Perry JR, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514:92–97. - PMC - PubMed

[7] Lunetta KL, et al. Rare coding variants and X-linked loci associated with age at menarche. Nat. Commun. 2015;6:7756. - PMC - PubMed

[8] Lunetta KL, et al. Rare coding variants and X-linked loci associated with age at menarche. Nat. Commun. 2015;6:7756. - PMC - PubMed

[9] Day FR, et al. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat. Commun. 2015;6:8842. - PMC - PubMed

[10] Day FR, et al. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat. Commun. 2015;6:8842. - PMC - PubMed

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

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

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