Format

Send to

Choose Destination
Nat Genet. 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.

Day FR1, Thompson DJ2, Helgason H3,4, Chasman DI5,6, Finucane H7,8, Sulem P3, Ruth KS9, Whalen S10, Sarkar AK11,12, Albrecht E13, Altmaier E14,15, Amini M16, Barbieri CM17, Boutin T18, Campbell A19, Demerath E20, Giri A21,22, He C23,24, Hottenga JJ25, Karlsson R26, Kolcic I27, Loh PR7,28, Lunetta KL29,30, Mangino M31,32, Marco B33, McMahon G34, Medland SE35, Nolte IM16, Noordam R36, Nutile T37, Paternoster L34,38, Perjakova N39, Porcu E40, Rose LM5, Schraut KE41,42, Segrè AV43, Smith AV44,45, Stolk L46, Teumer A47, Andrulis IL48,49, Bandinelli S50, Beckmann MW51, Benitez J52,53, Bergmann S54,55, Bochud M56, Boerwinkle E57, Bojesen SE58,59,60, Bolla MK2, Brand JS26, Brauch H61,62,63, Brenner H63,64,65, Broer L46, Brüning T66, Buring JE5,6, Campbell H42, Catamo E67, Chanock S68, Chenevix-Trench G69, Corre T54,55,56, Couch FJ70, Cousminer DL71,72, Cox A73, Crisponi L40, Czene K26, Davey Smith G34,38, de Geus EJCN25, de Mutsert R74, De Vivo I7,75, Dennis J2, Devilee P76,77, Dos-Santos-Silva I78, Dunning AM79, Eriksson JG80, Fasching PA51,81, Fernández-Rhodes L82, Ferrucci L83, Flesch-Janys D84,85, Franke L86, Gabrielson M26, Gandin I33, Giles GG87,88, Grallert H14,15,89, Gudbjartsson DF3,4, Guénel P90, Hall P26, Hallberg E91, Hamann U92, Harris TB93, Hartman CA94, Heiss G82, Hooning MJ95, Hopper JL88, Hu F75,96, Hunter DJ7,75,96, Ikram MA97, Im HK98, Järvelin MR99,100,101,102,103, Joshi PK42, Karasik D6,104, Kellis M11,12, Kutalik Z54,56, LaChance G31, Lambrechts D105,106, Langenberg C1, Launer LJ93, Laven JSE107, Lenarduzzi S67, Li J26, Lind PA35, Lindstrom S108, Liu Y109, Luan J1, Mägi R39, Mannermaa A110,111,112, Mbarek H25, McCarthy MI113,114,115, Meisinger C14,116, Meitinger T117, Menni C31, Metspalu A39, Michailidou K2,118, Milani L39, Milne RL87,88, Montgomery GW119, Mulligan AM120,121, Nalls MA122, Navarro P18, Nevanlinna H123, Nyholt DR124, Oldehinkel AJ125, O'Mara TA69, Padmanabhan S126, Palotie A28,127,128,129,130,131, Pedersen N26, Peters A14,89, Peto J78, Pharoah PDP2,79, Pouta A132, Radice P133, Rahman I134, Ring SM34,38, Robino A67, Rosendaal FR74, Rudan I42, Rueedi R54,55, Ruggiero D37, Sala CF17, Schmidt MK135,136, Scott RA1, Shah M79, Sorice R37, Southey MC137, Sovio U99,138, Stampfer M7,75, Steri M40, Strauch K13,139, Tanaka T83, Tikkanen E131,140, Timpson NJ34,38, Traglia M17, Truong T90, Tyrer JP79, Uitterlinden AG46,97, Edwards DRV22,141,142, Vitart V18, Völker U143, Vollenweider P144, Wang Q2, Widen E131, van Dijk KW77,145,146, Willemsen G25, Winqvist R147,148, Wolffenbuttel BHR149, Zhao JH1, Zoledziewska M40, Zygmunt M150, Alizadeh BZ16, Boomsma DI25, Ciullo M37, Cucca F40,151, Esko T28,39, Franceschini N82, Gieger C14,15,89, Gudnason V44,45, Hayward C18, Kraft P7,152, Lawlor DA34,38, Magnusson PKE26, Martin NG35, Mook-Kanamori DO74,153, Nohr EA154, Polasek O27, Porteous D19, Price AL7,8,28, Ridker PM5,6, Snieder H16, Spector TD31, Stöckl D14,155, Toniolo D17, Ulivi S67, Visser JA46, Völzke H47, Wareham NJ1, Wilson JF18,42; LifeLines Cohort Study; InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL consortium, Spurdle AB69, Thorsteindottir U3,44, Pollard KS10,156, Easton DF2,79, Tung JY157, Chang-Claude J158,159, Hinds D157, Murray A9, Murabito JM30,160, Stefansson K3,44, Ong KK1,161, Perry JRB1.

Author information

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.

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.

PMID:
28436984
PMCID:
PMC5841952
DOI:
10.1038/ng.3841
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center