. 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

Felix R Day^#¹, Katherine S Ruth^#², Deborah J Thompson^#³, Kathryn L Lunetta^{4

5}, Natalia Pervjakova^{6

7}, Daniel I Chasman^{8

9}, Lisette Stolk^{10

11}, Hilary K Finucane^{12

13}, Patrick Sulem¹⁴, Brendan Bulik-Sullivan^{15

16

17}, Tõnu Esko^{6

18

19

20}, Andrew D Johnson⁵, Cathy E Elks¹, Nora Franceschini²¹, Chunyan He^{22

23}, Elisabeth Altmaier^{24

25

26}, Jennifer A Brody²⁷, Lude L Franke²⁸, Jennifer E Huffman^{5

29}, Margaux F Keller³⁰, Patrick F McArdle³¹, Teresa Nutile³², Eleonora Porcu^{33

34

35}, Antonietta Robino³⁶, Lynda M Rose⁸, Ursula M Schick³⁷, Jennifer A Smith³⁸, Alexander Teumer³⁹, Michela Traglia⁴⁰, Dragana Vuckovic^{36

41}, Jie Yao⁴², Wei Zhao³⁸, Eva Albrecht²⁵, Najaf Amin⁴³, Tanguy Corre^{44

45}, Jouke-Jan Hottenga⁴⁶, Massimo Mangino^{47

48}, Albert V Smith^{49

50}, Toshiko Tanaka⁵¹, Goncalo Abecasis³⁵, Irene L Andrulis^{52

53}, Hoda Anton-Culver⁵⁴, Antonis C Antoniou³, Volker Arndt⁵⁵, Alice M Arnold⁵⁶, Caterina Barbieri^{36

40}, Matthias W Beckmann⁵⁷, Alicia Beeghly-Fadiel⁵⁸, Javier Benitez^{59

60}, Leslie Bernstein⁶¹, Suzette J Bielinski⁶², Carl Blomqvist⁶³, Eric Boerwinkle^{64

65}, Natalia V Bogdanova⁶⁶, Stig E Bojesen^{67

68}, Manjeet K Bolla³, Anne-Lise Borresen-Dale^{69

70}, Thibaud S Boutin²⁹, Hiltrud Brauch^{71

72

73}, Hermann Brenner^{55

73

74}, Thomas Brüning⁷⁵, Barbara Burwinkel^{76

77}, Archie Campbell⁷⁸, Harry Campbell⁷⁹, Stephen J Chanock⁸⁰, J Ross Chapman⁸¹, Yii-Der Ida Chen⁴², Georgia Chenevix-Trench⁸², Fergus J Couch⁸³, Andrea D Coviello⁸⁴, Angela Cox⁸⁵, Kamila Czene⁸⁶, Hatef Darabi⁸⁶, Immaculata De Vivo^{12

87}, Ellen W Demerath⁸⁸, Joe Dennis³, Peter Devilee^{89

90}, Thilo Dörk⁹¹, Isabel Dos-Santos-Silva⁹², Alison M Dunning⁹³, John D Eicher⁵, Peter A Fasching^{57

94}, Jessica D Faul⁹⁵, Jonine Figueroa⁹⁶, Dieter Flesch-Janys^{97

98}, Ilaria Gandin^{36

41}, Melissa E Garcia⁹⁹, Montserrat García-Closas^{100

101}, Graham G Giles^{102

103}, Giorgia G Girotto⁴¹, Mark S Goldberg^{104

105}, Anna González-Neira⁵⁹, Mark O Goodarzi¹⁰⁶, Megan L Grove⁶⁴, Daniel F Gudbjartsson^{14

107}, Pascal Guénel^{108

109}, Xiuqing Guo⁴², Christopher A Haiman¹¹⁰, Per Hall⁸⁶, Ute Hamann¹¹¹, Brian E Henderson¹¹⁰, Lynne J Hocking¹¹², Albert Hofman⁴³, Georg Homuth¹¹³, Maartje J Hooning¹¹⁴, John L Hopper¹⁰², Frank B Hu^{12

87

115}, Jinyan Huang¹¹⁶, Keith Humphreys⁸⁶, David J Hunter^{12

20

87

115}, Anna Jakubowska¹¹⁷, Samuel E Jones², Maria Kabisch¹¹¹, David Karasik^{9

118}, Julia A Knight^{119

120}, Ivana Kolcic¹²¹, Charles Kooperberg³⁷, Veli-Matti Kosma^{122

123

124}, Jennifer Kriebel^{24

26

125}, Vessela Kristensen^{69

70

126}, Diether Lambrechts^{127

128}, Claudia Langenberg¹, Jingmei Li⁸⁶, Xin Li¹², Sara Lindström¹², Yongmei Liu¹²⁹, Jian'an Luan¹, Jan Lubinski¹¹⁷, Reedik Mägi⁶, Arto Mannermaa^{122

123

124}, Judith Manz^{24

26}, Sara Margolin¹³⁰, Jonathan Marten²⁹, Nicholas G Martin¹³¹, Corrado Masciullo⁴⁰, Alfons Meindl¹³², Kyriaki Michailidou³, Evelin Mihailov⁶, Lili Milani⁶, Roger L Milne^{102

103}, Martina Müller-Nurasyid^{25

133

134}, Michael Nalls¹³⁵, Ben M Neale^{15

16

17}, Heli Nevanlinna¹³⁶, Patrick Neven¹³⁷, Anne B Newman^{138

139

140}, Børge G Nordestgaard^{67

68}, Janet E Olson⁶², Sandosh Padmanabhan¹⁴¹, Paolo Peterlongo¹⁴², Ulrike Peters³⁷, Astrid Petersmann¹⁴³, Julian Peto⁹², Paul D P Pharoah^{3

93}, Nicola N Pirastu^{36

41}, Ailith Pirie³, Giorgio Pistis^{33

34

35}, Ozren Polasek¹²¹, David Porteous⁷⁸, Bruce M Psaty^{27

144

145

146}, Katri Pylkäs^{147

148}, Paolo Radice¹⁴⁹, Leslie J Raffel^{150

151}, Fernando Rivadeneira^{10

11

43}, Igor Rudan⁷⁹, Anja Rudolph¹⁵², Daniela Ruggiero³², Cinzia F Sala⁴⁰, Serena Sanna³³, Elinor J Sawyer¹⁵³, David Schlessinger¹⁵⁴, Marjanka K Schmidt¹⁵⁵, Frank Schmidt¹¹³, Rita K Schmutzler^{156

157

158}, Minouk J Schoemaker¹⁰⁰, Robert A Scott¹, Caroline M Seynaeve¹¹⁴, Jacques Simard¹⁵⁹, Rossella Sorice³², Melissa C Southey¹⁶⁰, Doris Stöckl²⁶, Konstantin Strauch^{25

161}, Anthony Swerdlow^{100

162}, Kent D Taylor⁴², Unnur Thorsteinsdottir^{14

50}, Amanda E Toland¹⁶³, Ian Tomlinson^{81

164}, Thérèse Truong^{108

109}, Laufey Tryggvadottir¹⁶⁵, Stephen T Turner¹⁶⁶, Diego Vozzi³⁶, Qin Wang³, Melissa Wellons¹⁶⁷, Gonneke Willemsen⁴⁶, James F Wilson^{29

79}, Robert Winqvist^{147

148}, Bruce B H R Wolffenbuttel^{168

169}, Alan F Wright²⁹, Drakoulis Yannoukakos¹⁷⁰, Tatijana Zemunik¹²¹, Wei Zheng⁵⁸, Marek Zygmunt¹⁷¹, Sven Bergmann^{44

45}, Dorret I Boomsma⁴⁶, Julie E Buring^{8

9}, Luigi Ferrucci⁵¹, Grant W Montgomery¹³¹, Vilmundur Gudnason^{49

50}, Tim D Spector⁴⁷, Cornelia M van Duijn⁴³, Behrooz Z Alizadeh¹⁷², Marina Ciullo³², Laura Crisponi³³, Douglas F Easton^{3

93}, Paolo P Gasparini^{36

41}, Christian Gieger^{24

25

26}, Tamara B Harris⁹⁹, Caroline Hayward²⁹, Sharon L R Kardia³⁸, Peter Kraft^{12

173}, Barbara McKnight⁵⁶, Andres Metspalu⁶, Alanna C Morrison⁶⁴, Alex P Reiner^{37

144}, Paul M Ridker^{8

9}, Jerome I Rotter⁴², Daniela Toniolo⁴⁰, André G Uitterlinden^{10

11

43}, Sheila Ulivi³⁶, Henry Völzke³⁹, Nicholas J Wareham¹, David R Weir⁹⁵, Laura M Yerges-Armstrong³¹; PRACTICAL consortium; kConFab Investigators; AOCS Investigators; Generation Scotland; EPIC-InterAct Consortium; LifeLines Cohort Study; Alkes L Price¹², Kari Stefansson^{14

50}, Jenny A Visser¹⁰, Ken K Ong^{1

174}, Jenny Chang-Claude¹⁵², Joanne M Murabito^{5

175}, John R B Perry¹, Anna Murray²

Affiliations

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.

PMID: 26414677
PMCID: PMC4661791
DOI: 10.1038/ng.3412

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

Felix R Day et al. Nat Genet. 2015 Nov.

. 2015 Nov;47(11):1294-1303.

doi: 10.1038/ng.3412. Epub 2015 Sep 28.

Authors

Affiliations

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.

PMID: 26414677
PMCID: PMC4661791
DOI: 10.1038/ng.3412

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.

PubMed Disclaimer

Figures

**Figure 1**
Miami plot of HapMap and exome SNP associations. Log-transformed P values are shown for association with ANM for SNPs from HapMap 2 (top; pink) and SNPs from the meta-analysis of exome chip data (bottom; blue). Previously known signals are shown in gray, and newly discovered signals are shown in red (HapMap 2) or purple (exome chip and HapMap 2). The yellow lines correspond to genome-wide significant levels in each direction; the gray lines indicate where the y axis has been truncated.

**Figure 2**
Multiple signals at HELB and relationship to DNA helicase B protein sequence. Positions are given in Build 37 coordinates of the reference genome. The top signal from the exome chip analysis maps to an acidic motif of DNA helicase B and results in the replacement of an acidic aspartate residue by a nonpolar glycine residue. Concurrent alteration of three acidic amino acids, (including the aspartate residue identified by the exome chip analysis) to nonpolar residues has been shown to reduce RPA binding (8)

**Figure 3**
Classification of genes identified as being involved in the DNA damage response, at genetic loci associated with ANM.

See this image and copyright information in PMC

References

1. Hartge P. Genetics of reproductive lifespan. Nat Genet. 2009;41:637–638. - PubMed
1. Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian reserve to predict age at menopause. Maturitas. 2009;63:280–91. - PubMed
1. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8:141–54. - PubMed
1. Stolk L, et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nature genetics. 2012;44:260–8. - PMC - PubMed
1. Perry JR, et al. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Hum Mol Genet. 2014 - PMC - PubMed

Methods-only references

1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1. - PMC - PubMed
1. Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. - PMC - PubMed
1. Zhou JJ, et al. A comparative analysis of family-based and population-based association tests using whole genome sequence data. BMC Proc. 2014;8:S33. - PMC - PubMed
1. Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88:76–82. - PMC - PubMed
1. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5. - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Methods-only references

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous