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Nat Commun. 2015 Aug 4;6:7756. doi: 10.1038/ncomms8756.

Rare coding variants and X-linked loci associated with age at menarche.

Author information

1
1] Boston University School of Public Health, Department of Biostatistics, Boston, Massachusetts 02118, USA [2] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.
2
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
3
deCODE genetics/Amgen, Inc., Reykjavik IS-101, Iceland.
4
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
5
23andMe Inc., 1390 Shorebird Way, Mountain View, California 94043, USA.
6
1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia [2] Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA [3] Department of Genetics, Harvard Medical School, Boston, MA 02115, USA [4] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140, Cambridge, MA 02142, USA.
7
1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany [2] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
8
1] Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA [2] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
9
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
10
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
11
1] Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Sardinia 09042, Italy [2] University of Sassari, Department of Biomedical Sciences, Sassari, Sassari 07100, Italy [3] Center for Statistical Genetics, Ann Arbor, University of Michigan, Michigan 48109-2029, USA.
12
Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste 34137, Italy.
13
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
14
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA 98109-1024, USA.
15
Department of Internal Medicine, Erasmus MC, Rotterdam 3015GE, the Netherlands.
16
Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
17
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, UK.
18
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy.
19
School of Women's and Infants' Health, The University of Western Australia, WA-6009, Australia.
20
Program in Personalized Medicine, Division of Endocrinology, Diabetes and Nutrition-University of Maryland School of Medicine, Baltimore, MD 21201, USA.
21
Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, MA, USA.
22
1] Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Sardinia 09042, Italy [2] University of Sassari, Department of Biomedical Sciences, Sassari, Sassari 07100, Italy.
23
Division of Epidemiology &Community Health, University of Minnesotta, Minneapolis, MN 55455, USA.
24
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
25
1] Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste 34137, Italy [2] Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Trieste 34149, Italy.
26
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
27
1] deCODE genetics/Amgen, Inc., Reykjavik IS-101, Iceland [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik IS-101, Iceland.
28
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen AB25 2ZD, UK.
29
Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, Rotterdam 3015 GE, the Netherlands.
30
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
31
Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
32
1] Hebrew SeniorLife Institute for Aging Research, Boston, MA 02131, USA [2] Harvard Medical School, Boston, MA 02115, USA.
33
1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany [2] German Center for Diabetes Research, Neuherberg 85764, Germany.
34
1] Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA [2] Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA.
35
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
36
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
37
British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
38
Faculty of Medicine, University of Split, Split, Croatia.
39
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
40
1] Department of Internal Medicine, Erasmus MC, Rotterdam 3015GE, the Netherlands [2] Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, Rotterdam 3015 GE, the Netherlands.
41
Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.
42
National Institute on Aging, Intramural Research Program, Baltimore, MD 20892, USA.
43
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
44
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany.
45
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
46
Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald 17475, Germany.
47
1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215 [2] Harvard Medical School, Boston, MA 02115, USA.
48
Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Sardinia 09042, Italy.
49
1] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, UK [2] Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
50
1] Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA [3] Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
51
Departments of Epidemiology and Medicine Brown University, Brown University, Providence, RI 02912, USA.
52
1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia [2] Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
53
1] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
54
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA.
55
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
56
1] deCODE genetics/Amgen, Inc., Reykjavik IS-101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
57
1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA 02118, USA.
58
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] Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
59
1] The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK [2] University of Cambridge Metabolic Research Laboratories, Cambridge CB2 0QQ, UK.
60
The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
61
1] Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, OX3 7LJ, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [3] Oxford NIHR Biomedical Research Centre, Oxford OX3 7LJ, UK.
62
1] Public Health Division of Gipuzkoa, San Sebastian 20013, Spain [2] Instituto BIO-Donostia, Basque Government, Donostia, San Sebastian 20014, Spain [3] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.
63
1] Inserm, CESP, U1018, Villejuif, cedex 94807, France [2] Univ Paris-Sud, UMRS 1018, Villejuif F-94805, France.
64
1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain [2] Navarre Public Health Institute (ISPN), Pamplona 31003, Spain.
65
German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal 14558, Germany.
66
1] Department of Clinical Sciences, Lund University, Malmö S-205 02, Sweden [2] Department of Public Health and Clinical Medicine, Umeå University, Umeå 90187, Sweden.
67
Catalan Institute of Oncology (ICO), Badalona, Barcelona 08916, Spain.
68
Epidemiology and Prevention Unit, Milan 20133, Italy.
69
German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
70
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF, UK.
71
1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain [2] Department of Epidemiology, Murcia Regional Health Council, Murcia 30008, Spain [3] Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Espinardo 30100, Spain.
72
Department of Clinical Sciences, Lund University, Malmö S-205 02, Sweden.
73
1] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus C DK-8000, Denmark [2] Aalborg University Hospital, Aalborg 9100, Denmark.
74
Cancer Research and Prevention Institute (ISPO), Florence 50141, Italy.
75
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples 80131, Italy.
76
Public Health Directorate, Oviedo-Asturias 33006, Spain.
77
Department of Public Health and Clinical Medicine, Umeå University, Umeå 90187, Sweden.
78
1] Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino 10126, Italy [2] Human Genetics Foundation (HuGeF), Torino 10126, Italy.
79
1] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain [2] Andalusian School of Public Health, Granada 18080, Spain [3] Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada 18012, Spain.
80
International Agency for Research on Cancer, Lyon, Cedex 08 69372, France.
81
Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
82
1] ASP, Ragusa 97100, Italy [2] Ragusa Cancer Registry, Aire Onlus, Ragusa 97100, Italy.
83
National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, The Netherlands.
84
University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands.
85
School of Public Health, Imperial College London, W2 1PG, UK.
86
1] Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK [2] Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
87
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
88
1] Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [3] Department of Psychology, University of Edinburgh, EH8 9JZ, UK.
89
1] Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK [2] Division of Psychiatry, University of Edinburgh, Edinburgh, EH10 5HF, UK.

Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

PMID:
26239645
PMCID:
PMC4538850
DOI:
10.1038/ncomms8756
[Indexed for MEDLINE]
Free PMC Article

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