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Nature. 2014 Oct 2;514(7520):92-97. doi: 10.1038/nature13545. Epub 2014 Jul 23.

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

Perry JR#1,2,3,4, Day F#1, Elks CE#1, Sulem P#5, Thompson DJ6, Ferreira T3, He C7,8, Chasman DI9,10, Esko T11,12,13,14, Thorleifsson G5, Albrecht E15, Ang WQ16, Corre T17,18, Cousminer DL19, Feenstra B20, Franceschini N21, Ganna A22, Johnson AD23, Kjellqvist S24, Lunetta KL23,25, McMahon G26,27, Nolte IM28, Paternoster L26, Porcu E29,30, Smith AV31,32, Stolk L33,34, Teumer A35, Tšernikova N11,36, Tikkanen E19,37, Ulivi S38, Wagner EK7,8, Amin N39, Bierut LJ40, Byrne EM41,42, Hottenga JJ43, Koller DL44, Mangino M4, Pers TH12,13,45,46, Yerges-Armstrong LM47, Zhao JH1, Andrulis IL48,49, Anton-Culver H50, Atsma F51, Bandinelli S52,53, Beckmann MW54, Benitez J55,56, Blomqvist C57, Bojesen SE58,59, Bolla MK6, Bonanni B60, Brauch H61,62, Brenner H63,64, Buring JE9,10, Chang-Claude J65, Chanock S66, Chen J67,68, Chenevix-Trench G69, Collée JM70, Couch FJ71, Couper D72, Coveillo AD73, Cox A74, Czene K22, D'adamo AP38,75, Smith GD26,27, De Vivo I76,77, Demerath EW78, Dennis J6, Devilee P79, Dieffenbach AK63,64, Dunning AM80, Eiriksdottir G31, Eriksson JG81,82,83,84, Fasching PA54, Ferrucci L85, Flesch-Janys D86, Flyger H87, Foroud T44, Franke L88, Garcia ME89, García-Closas M90,91, Geller F20, de Geus EE43,92, Giles GG93,94, Gudbjartsson DF5,95, Gudnason V31,32, Guénel P96,97, Guo S98, Hall P22, Hamann U99, Haring R100, Hartman CA101, Heath AC102, Hofman A103, Hooning MJ104, Hopper JL94, Hu FB76,77,105, Hunter DJ13,76,77, Karasik D10,106, Kiel DP106,107, Knight JA108,109, Kosma VM110,111, Kutalik Z17,18, Lai S29, Lambrechts D112,113, Lindblom A114, Mägi R11, Magnusson PK22, Mannermaa A110,111, Martin NG69, Masson G5, McArdle PF47, McArdle WL27, Melbye M20,115, Michailidou K6, Mihailov E11,36, Milani L11, Milne RL93,94, Nevanlinna H116, Neven P117, Nohr EA118, Oldehinkel AJ119, Oostra BA39, Palotie A19,120,121,122, Peacock M123, Pedersen NL22, Peterlongo P124, Peto J125, Pharoah PD80, Postma DS126, Pouta A81,127, Pylkäs K128, Radice P129, Ring S26,27, Rivadeneira F33,34,103, Robino A38,75, Rose LM9, Rudolph A65, Salomaa V81, Sanna S29, Schlessinger D130, Schmidt MK131, Southey MC132, Sovio U133,134, Stampfer MJ76,77,105, Stöckl D135,136, Storniolo AM123, Timpson NJ26,27, Tyrer J80, Visser JA33, Vollenweider P137, Völzke H138,139, Waeber G137, Waldenberger M140, Wallaschofski H100,139, Wang Q6, Willemsen G43, Winqvist R128, Wolffenbuttel BH141, Wright MJ142; Australian Ovarian Cancer Study; GENICA Network; kConFab; LifeLines Cohort Study; InterAct Consortium; Early Growth Genetics (EGG) Consortium, Boomsma DI43, Econs MJ44,123, Khaw KT143, Loos RJ1,144, McCarthy MI3,145,146, Montgomery GW142, Rice JP40, Streeten EA47,147, Thorsteinsdottir U5,95, van Duijn CM34,39,148, Alizadeh BZ28, Bergmann S17,18, Boerwinkle E149, Boyd HA20, Crisponi L29, Gasparini P38,75, Gieger C15, Harris TB89, Ingelsson E150, Järvelin MR133,151,152,153,154, Kraft P76,155, Lawlor D26,27, Metspalu A11,36, Pennell CE16, Ridker PM9,10, Snieder H28, Sørensen TI156,157, Spector TD4, Strachan DP158, Uitterlinden AG33,34,103, Wareham NJ1, Widen E19, Zygmunt M159, Murray A2, Easton DF6, Stefansson K#5,95, Murabito JM#23,160, Ong KK#1,161.

Author information

1
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
2
University of Exeter Medical School, University of Exeter, Exeter, UK EX1 2LU.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
5
deCODE Genetics, Reykjavik, Iceland.
6
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK.
7
Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
8
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
9
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
10
Harvard Medical School, Boston, MA 02115.
11
Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
12
Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
13
Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge 02142, MA, USA.
14
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
15
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
16
School of Women's and Infants' Health, The University of Western Australia.
17
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
18
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
19
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
20
Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark.
21
Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
22
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
23
NHLBI's and Boston University's Framingham Heart Study, Framingham, MA.
24
Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
25
Boston University School of Public Health, Department of Biostatistics. Boston, MA.
26
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
27
School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
28
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
29
Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
30
University of Sassari, Dept. Of Biomedical Sciences, Sassari, Italy.
31
Icelandic Heart Association, Kopavogur, Iceland.
32
University of Iceland, Reykjavik, Iceland.
33
Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
34
Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands.
35
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.
36
Department of Biotechnology, University of Tartu, Tartu, 51010, Estonia.
37
Hjelt Institute, University of Helsinki, Finland.
38
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy.
39
Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
40
Dept. of Psychiatry, Washington University, St. Louis, MO 63110.
41
The University of Queensland, Queensland Brain Institute, St.Lucia, QLD, Australia.
42
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
43
Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
44
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana USA.
45
Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, US.
46
Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, Lyngby 2800, Denmark.
47
Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition - University of Maryland School of Medicine, USA. Baltimore, MD 21201.
48
Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
49
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
50
Department of Epidemiology, University of California Irvine, Irvine, California, USA.
51
Sanquin Research, Nijmegen, The Netherlands.
52
Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.
53
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
54
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
55
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
56
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
57
Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
61
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart.
62
University of Tübingen, Germany.
63
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
64
German Cancer Consortium (DKTK), Heidelberg, Germany.
65
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
66
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
67
Departments of Anatomy and Neurological Surgery, Indiana University school of Medicine, Indianapolis, IN 46202, USA.
68
Stark Neuroscience Research Center, Indiana University school of Medicine, Indianapolis, IN 46202, USA.
69
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
70
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
71
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
72
Department of Biostatistics, University of North Carolina, Chapel Hill, NC.
73
Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, MA.
74
Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, UK.
75
Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Italy.
76
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
77
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
78
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minn., USA.
79
Department of Human Genetics & Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
80
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.
81
National Institute for Health and Welfare, Finland.
82
Department of General Practice and Primary health Care, University of Helsinki, Finland.
83
Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
84
Folkhalsan Research Centre, Helsinki, Finland.
85
Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America.
86
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
87
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
88
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
89
National Insitute on Aging, National Institutes of Health, Baltimore, MD 20892, USA.
90
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
91
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
92
EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands.
93
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
94
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
95
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
96
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France.
97
University Paris-Sud, UMRS 1018, Villejuif, France.
98
Department of Obstetrics and Gynecology, Southern Medical University, Guangzhou, China.
99
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
100
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
101
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
102
Washington University, Department of Psychiatry, St.Louis, Missouri, USA.
103
Department of Epidemiology, Erasmus MC, Rotterdan, the Netherlands.
104
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
105
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
106
Hebrew SeniorLife Institute for Aging Research, Boston, MA.
107
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
108
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
109
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
110
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
111
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
112
Vesalius Research Center (VRC), VIB, Leuven, Belgium.
113
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
114
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
115
Department of Medicine, Stanford School of Medicine, Stanford, USA.
116
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
117
KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Belgium.
118
Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern denmark, DK.
119
Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
120
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
121
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
122
Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
123
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana USA.
124
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
125
Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
126
University Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, Groningen, The Netherlands.
127
Department of Obstetrics and Gynecology, Oulu University Hospital, Finland.
128
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, Oulu, Finland.
129
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.
130
National Institute on Aging, Intramural Research Program, Baltimore, MD, USA.
131
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
132
Department of Pathology, The University of Melbourne, Melbourne, Australia.
133
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK.
134
Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom.
135
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
136
Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians- University, Munich, Germany.
137
Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
138
Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
139
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, 17475 Greifswald, Germany.
140
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
141
Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
142
Queensland Insitute of Medical Research, Brisbane, Queensland, Australia.
143
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, CB2 0QQ, UK.
144
Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1003, New York, NY 10029, USA.
145
NIHR Oxford Biomedical Research Centre, Churchill Hospital, OX3 7LE Oxford, UK.
146
Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, Churchill Hospital, OX37LJ Oxford, UK.
147
Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, USA. Baltimore, MD 21201.
148
Centre of Medical Systems Biology, Leiden, the Netherlands.
149
Human Genetics Center and Div. of Epidemiology, University of Houston, TX.
150
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
151
Institute of Health Sciences, P.O.Box 5000, FI-90014 University of Oulu, Finland.
152
Biocenter Oulu, P.O.Box 5000, Aapistie 5A, FI-90014 University of Oulu, Finland.
153
Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland.
154
Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O.Box 20, FI-90220 Oulu, 90029 OYS, Finland.
155
Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
156
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
157
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark.
158
Division of Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
159
Department of Obstetrics and Gynecology, University Medicine Greifswald, 17475 Greifswald, Germany.
160
Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA.
161
Department of Paediatrics,University of Cambridge,Cambridge,UK.
#
Contributed equally

Abstract

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.

PMID:
25231870
PMCID:
PMC4185210
DOI:
10.1038/nature13545
[Indexed for MEDLINE]
Free PMC Article

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