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Nat Genet. 2015 Nov;47(11):1294-1303. doi: 10.1038/ng.3412. Epub 2015 Sep 28.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Day FR#1, Ruth KS#2, Thompson DJ#3, Lunetta KL4,5, Pervjakova N6,7, Chasman DI8,9, Stolk L10,11, Finucane HK12,13, Sulem P14, Bulik-Sullivan B15,16,17, Esko T6,18,19,20, Johnson AD5, Elks CE1, Franceschini N21, He C22,23, Altmaier E24,25,26, Brody JA27, Franke LL28, Huffman JE5,29, Keller MF30, McArdle PF31, Nutile T32, Porcu E33,34,35, Robino A36, Rose LM8, Schick UM37, Smith JA38, Teumer A39, Traglia M40, Vuckovic D36,41, Yao J42, Zhao W38, Albrecht E25, Amin N43, Corre T44,45, Hottenga JJ46, Mangino M47,48, Smith AV49,50, Tanaka T51, Abecasis G35, Andrulis IL52,53, Anton-Culver H54, Antoniou AC3, Arndt V55, Arnold AM56, Barbieri C36,40, Beckmann MW57, Beeghly-Fadiel A58, Benitez J59,60, Bernstein L61, Bielinski SJ62, Blomqvist C63, Boerwinkle E64,65, Bogdanova NV66, Bojesen SE67,68, Bolla MK3, Borresen-Dale AL69,70, Boutin TS29, Brauch H71,72,73, Brenner H55,73,74, Brüning T75, Burwinkel B76,77, Campbell A78, Campbell H79, Chanock SJ80, Chapman JR81, Chen YI42, Chenevix-Trench G82, Couch FJ83, Coviello AD84, Cox A85, Czene K86, Darabi H86, De Vivo I12,87, Demerath EW88, Dennis J3, Devilee P89,90, Dörk T91, Dos-Santos-Silva I92, Dunning AM93, Eicher JD5, Fasching PA57,94, Faul JD95, Figueroa J96, Flesch-Janys D97,98, Gandin I36,41, Garcia ME99, García-Closas M100,101, Giles GG102,103, Girotto GG41, Goldberg MS104,105, González-Neira A59, Goodarzi MO106, Grove ML64, Gudbjartsson DF14,107, Guénel P108,109, Guo X42, Haiman CA110, Hall P86, Hamann U111, Henderson BE110, Hocking LJ112, Hofman A43, Homuth G113, Hooning MJ114, Hopper JL102, Hu FB12,87,115, Huang J116, Humphreys K86, Hunter DJ12,20,87,115, Jakubowska A117, Jones SE2, Kabisch M111, Karasik D9,118, Knight JA119,120, Kolcic I121, Kooperberg C37, Kosma VM122,123,124, Kriebel J24,26,125, Kristensen V69,70,126, Lambrechts D127,128, Langenberg C1, Li J86, Li X12, Lindström S12, Liu Y129, Luan J1, Lubinski J117, Mägi R6, Mannermaa A122,123,124, Manz J24,26, Margolin S130, Marten J29, Martin NG131, Masciullo C40, Meindl A132, Michailidou K3, Mihailov E6, Milani L6, Milne RL102,103, Müller-Nurasyid M25,133,134, Nalls M135, Neale BM15,16,17, Nevanlinna H136, Neven P137, Newman AB138,139,140, Nordestgaard BG67,68, Olson JE62, Padmanabhan S141, Peterlongo P142, Peters U37, Petersmann A143, Peto J92, Pharoah PDP3,93, Pirastu NN36,41, Pirie A3, Pistis G33,34,35, Polasek O121, Porteous D78, Psaty BM27,144,145,146, Pylkäs K147,148, Radice P149, Raffel LJ150,151, Rivadeneira F10,11,43, Rudan I79, Rudolph A152, Ruggiero D32, Sala CF40, Sanna S33, Sawyer EJ153, Schlessinger D154, Schmidt MK155, Schmidt F113, Schmutzler RK156,157,158, Schoemaker MJ100, Scott RA1, Seynaeve CM114, Simard J159, Sorice R32, Southey MC160, Stöckl D26, Strauch K25,161, Swerdlow A100,162, Taylor KD42, Thorsteinsdottir U14,50, Toland AE163, Tomlinson I81,164, Truong T108,109, Tryggvadottir L165, Turner ST166, Vozzi D36, Wang Q3, Wellons M167, Willemsen G46, Wilson JF29,79, Winqvist R147,148, Wolffenbuttel BBHR168,169, Wright AF29, Yannoukakos D170, Zemunik T121, Zheng W58, Zygmunt M171, Bergmann S44,45, Boomsma DI46, Buring JE8,9, Ferrucci L51, Montgomery GW131, Gudnason V49,50, Spector TD47, van Duijn CM43, Alizadeh BZ172, Ciullo M32, Crisponi L33, Easton DF3,93, Gasparini PP36,41, Gieger C24,25,26, Harris TB99, Hayward C29, Kardia SLR38, Kraft P12,173, McKnight B56, Metspalu A6, Morrison AC64, Reiner AP37,144, Ridker PM8,9, Rotter JI42, Toniolo D40, Uitterlinden AG10,11,43, Ulivi S36, Völzke H39, Wareham NJ1, Weir DR95, Yerges-Armstrong LM31; PRACTICAL consortium; kConFab Investigators; AOCS Investigators; Generation Scotland; EPIC-InterAct Consortium; LifeLines Cohort Study, Price AL12, Stefansson K14,50, Visser JA10, Ong KK1,174, Chang-Claude J152, Murabito JM5,175, Perry JRB1, Murray A2.

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
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, UK.
4
Boston University School of Public Health, Department of Biostatistics. Boston, Massachusetts 02118, USA.
5
NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.
6
Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
7
Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
8
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
9
Harvard Medical School, Boston, MA 02115, USA.
10
Department of Internal Medicine, Erasmus MC, 3015GE Rotterdam, the Netherlands.
11
Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands.
12
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
13
Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, USA.
14
deCODE genetics/Amgen, Inc., IS-101 Reykjavik, Iceland.
15
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
16
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
17
Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, US.
18
Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
19
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
20
Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge 02142, MA, USA.
21
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
22
Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
23
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
24
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
25
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
26
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
27
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle Washington 98101 USA.
28
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
29
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
30
Merck Pharmaceuticals, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
31
Program in Personalized Medicine, Division of Endocrinology, Diabetes and Nutrition - University of Maryland School of Medicine, USA. Baltimore, MD 21201.
32
Institute of Genetics and Biophysics - CNR, via Pietro Castellino 111, 80131, Naples, Italy.
33
Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy.
34
University of Sassari, Department of Biomedical Sciences, Sassari, 07100 Sassari, Italy.
35
Center for Statistical Genetics, Ann Arbor, University of Michigan, Michigan 48109-2029, USA.
36
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
37
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA 98109-1024, USA.
38
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
39
Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
40
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy.
41
Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, 34149 Trieste, Italy.
42
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
43
Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands.
44
Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.
45
Swiss Institute of Bioinformatics, CH-1015, Lausanne, Switzerland.
46
Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
47
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
48
National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
49
Icelandic Heart Association, Kopavogur, Iceland.
50
Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
51
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21224, United States of America.
52
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
53
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
54
Department of Epidemiology, University of California Irvine, Irvine, California, USA.
55
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
56
Department of Biostatistics, University of Washington, Seattle, WA, USA.
57
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
58
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
59
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
60
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
61
Beckman Research Institute of City of Hope, Duarte, CA, USA.
62
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
63
Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
64
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
65
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
66
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
67
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
68
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
69
Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway.
70
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
71
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
72
University of Tübingen, Tübingen, Germany.
73
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
74
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
75
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
76
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
77
Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
78
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
79
Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.
80
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
81
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
82
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
83
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
84
Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, MA.
85
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
86
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.
87
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
88
Division of Epidemiology & Community Health, University of Minnesotta, Minneapolis MN 55455.
89
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
90
Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
91
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
92
Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
93
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
94
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA.
95
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
96
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
97
Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
98
Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
99
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.
100
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
101
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
102
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
103
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
104
Department of Medicine, McGill University, Montreal, Canada.
105
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
106
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.
107
School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland.
108
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
109
University Paris-Sud, UMRS 1018, Villejuif, France.
110
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
111
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
112
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen AB25 2ZD, UK.
113
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.
114
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
115
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
116
State Key Laboratory of Medical Genomics,Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
117
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
118
Hebrew SeniorLife Institute for Aging Research, Boston, MA, 02131, USA.
119
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
120
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
121
Faculty of Medicine, University of Split, Split, Croatia.
122
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
123
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
124
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
125
German Center for Diabetes Research, 85764 Neuherberg, Germany.
126
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
127
Vesalius Research Center (VRC), VIB, Leuven, Belgium.
128
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
129
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine.
130
Department of Oncology - Pathology, Karolinska Institutet, Stockholm 17177, Sweden.
131
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
132
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
133
Department of Medicine I, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
134
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
135
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
136
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
137
KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Belgium.
138
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
139
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
140
Department of Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
141
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.
142
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
143
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
144
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195, USA.
145
Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.
146
Department of Health Services, University of Washington, Seattle, Washington 98101, USA.
147
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry, University of Oulu, Oulu, Finland.
148
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
149
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.
150
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
151
UCLA Clinical & Translational Science Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
152
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
153
Research Oncology, Guy's Hospital, King's College London, London, UK.
154
National Institute on Aging, Intramural Research Program, Baltimore, MD 20892, USA.
155
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
156
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
157
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
158
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
159
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
160
Department of Pathology, The University of Melbourne, Melbourne, Australia.
161
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
162
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
163
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
164
NIHR Oxford Biomedical Research Centre, Churchill Hospital, OX3 7LE Oxford, UK.
165
Icelandic Cancer Registry, Reykjavik, Iceland.
166
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
167
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37203, USA.
168
Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
169
LifeLines Cohort Study and Biobank, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
170
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
171
Department of Obstetrics and Gynecology, University Medicine Greifswald, 17475 Greifswald, Germany.
172
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
173
Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
174
Department of Paediatrics,University of Cambridge,Cambridge, CB2 0QQ, UK.
175
Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA 02118, USA.
#
Contributed equally

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

PMID:
26414677
PMCID:
PMC4661791
DOI:
10.1038/ng.3412
[Indexed for MEDLINE]
Free PMC Article

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