Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair
Felix R. Day(University of Cambridge), kConFab Investigators(University of Exeter), AOCS Investigators(University of Cambridge), Generation Scotland(Boston University), LifeLines Cohort Study(University of Tartu), Katherine S. Ruth(Brigham and Women's Hospital), Deborah J. Thompson(University of Cambridge), Kathryn L. Lunetta(Boston University), Natalia Pervjakova(deCODE Genetics (Iceland)), Daniel I. Chasman(Broad Institute), Lisette Stolk(Broad Institute), Hilary K. Finucane(Harvard University), Patrick Sulem(deCODE Genetics (Iceland)), Brendan Bulik‐Sullivan(Broad Institute), Tõnu Esko(Broad Institute), Andrew D. Johnson(Helmholtz Zentrum München), Cathy E. Elks(University of Washington), Nora Franceschini(University of North Carolina at Chapel Hill), Chunyan He(Indiana University Health), Elisabeth Altmaier(Merck & Co., Inc., Rahway, NJ, USA (United States)), Jennifer A. Brody(University of Maryland, Baltimore), Lude L Franke(University Medical Center Groningen), Jennifer E. Huffman(University of Sassari), Margaux F. Keller(Merck & Co., Inc., Rahway, NJ, USA (United States)), Patrick F. McArdle(University of Maryland, Baltimore), Teresa Nutile(Fred Hutch Cancer Center), Eleonora Porcu(University of Sassari), Antonietta Robino(Universitätsmedizin Greifswald), Lynda M. Rose(Brigham and Women's Hospital), Ursula M. Schick(University of Trieste), Jennifer A. Smith(University of Michigan), Alexander Teumer(University of Michigan), Michela Traglia(Helmholtz Zentrum München), Dragana Vuckovic(University of Trieste), Jie Yao(SIB Swiss Institute of Bioinformatics), Wei Zhao(University of Michigan), Eva Albrecht(King's College London), Najaf Amin(University of Iceland), Tanguy Corre(SIB Swiss Institute of Bioinformatics), Jouke‐Jan Hottenga(University of Michigan), Massimo Mangino(King's College London), Albert V. Smith(University of Iceland), Toshiko Tanaka(University of Cambridge), Gonçalo R. Abecasis(German Cancer Research Center), Irene L. Andrulis(University of Toronto), Hoda Anton‐Culver(University of California, Irvine), Antonis C. Antoniou(Friedrich-Alexander-Universität Erlangen-Nürnberg), Volker Arndt(German Cancer Research Center), Alice M. Arnold(University of Washington), Caterina Barbieri(IRCCS Materno Infantile Burlo Garofolo), Matthias W. Beckmann(Friedrich-Alexander-Universität Erlangen-Nürnberg), Alicia Beeghly‐Fadiel(University of Helsinki), Javier Benı́tez(Baylor College of Medicine), Leslie Bernstein(Medizinische Hochschule Hannover), Suzette J. Bielinski(University of Copenhagen), Carl Blomqvist(University of Helsinki), Eric Boerwinkle(Oslo University Hospital), Natalia Bogdanova(Medizinische Hochschule Hannover), Stig E. Bojesen(University of Copenhagen), Manjeet K. Bolla(German Cancer Research Center), Anne‐Lise Børresen‐Dale(Oslo University Hospital), Thibaud Boutin(German Cancer Research Center), Hiltrud Brauch(German Cancer Research Center), Hermann Brenner(German Cancer Research Center), Thomas Brüning(Institute for Prevention and Occupational Medicine), Barbara Burwinkel(Centre for Human Genetics), Archie Campbell(UCLA Medical Center), Harry Campbell(QIMR Berghofer Medical Research Institute), Stephen J. Chanock(Mayo Clinic in Arizona), J. Ross Chapman(Boston University), Yii-Der Ida Chen(UCLA Medical Center), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Fergus J. Couch(Karolinska Institutet), Andrea D. Coviello(Boston University), Angela Cox(University of Minnesota), Kamila Czene(University of Cambridge), Hatef Darabi(Leiden University Medical Center), Immaculata De Vivo(Brigham and Women's Hospital), Ellen W. Demerath(University of Minnesota), Joe Dennis(University of Cambridge), Peter Devilee(Leiden University Medical Center), Thilo Dörk(University of California, Los Angeles), Isabel dos‐Santos‐Silva(University of Michigan), Alison M. Dunning(University of Cambridge), John D. Eicher(Universität Hamburg), Peter A. Fasching(University of Trieste), Jessica D. Faul(University of Michigan), Jonine D. Figueroa(Institute of Cancer Research), Dieter Flesch‐Janys(Universität Hamburg), Ilaria Gandin(University of Trieste), Melissa E. Garcia(Royal Victoria Hospital), Montserrat García‐Closas(Institute of Cancer Research), Graham G. Giles(Cedars-Sinai Medical Center), Giorgia Girotto(University of Trieste), Mark S. Goldberg(deCODE Genetics (Iceland)), Anna González‐Neira(Université Paris-Sud), Mark O. Goodarzi(Cedars-Sinai Medical Center), Megan L. Grove(University of Southern California), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Pascal Guénel(Université Paris-Sud), Xiuqing Guo(University of Southern California), Christopher A. Haiman(University of Southern California), Per Hall(Karolinska Institutet), Ute Hamann(German Cancer Research Center), Brian E. Henderson(University of Southern California), Lynne J. Hocking(The University of Melbourne), Albert Hofman(Brigham and Women's Hospital), Georg Homuth(Universitätsmedizin Greifswald), Maartje J. Hooning(Erasmus MC), John L. Hopper(Broad Institute), Frank B. Hu(Brigham and Women's Hospital), Jinyan Huang(University of Exeter), Keith Humphreys(German Cancer Research Center), David J. Hunter(Broad Institute), Anna Jakubowska(Mount Sinai Hospital), Samuel E. Jones(University of Exeter), Maria Kabisch(German Cancer Research Center), David Karasik(Harvard University), Julia A. Knight(Mount Sinai Hospital), Ivana Kolčić(Oslo University Hospital), Charles Kooperberg(Fred Hutch Cancer Center), Veli‐Matti Kosma(University of Eastern Finland), Jennifer Kriebel(Karolinska Institutet), Vessela N. Kristensen(Oslo University Hospital), Diether Lambrechts(Harvard University), Claudia Langenberg(University of Cambridge), Jingmei Li(University of Cambridge), Xin Li(Harvard University), Sara Lindström(Harvard University), Ching‐Ti Liu(University of Eastern Finland), Jian’an Luan(University of Cambridge), Jan Lubiński(Karolinska Institutet), Reedik Mägi(Institute of Genetics and Cancer), Arto Mannermaa(University of Eastern Finland), Judith Manz(Helmholtz Zentrum München), Sara Margolin(Karolinska Institutet), Jonathan Marten(University of Cambridge), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Corrado Masciullo(University of Tartu), Alfons Meindl(The University of Melbourne), Kyriaki Michailidou(University of Cambridge), Evelin Mihailov(National Institute on Aging), Lili Milani(Broad Institute), Roger L. Milne(University of Helsinki), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Michael A. Nalls(University of Pittsburgh), Benjamin M Neale(Broad Institute), Heli Nevanlinna(University of Helsinki), Patrick Neven(University of Glasgow), Anne B. Newman(University of Pittsburgh), Børge G. Nordestgaard(University of Copenhagen), Janet E. Olson(Universitätsmedizin Greifswald), Sandosh Padmanabhan(London School of Hygiene & Tropical Medicine), Paolo Peterlongo(University of Cambridge), Ulrike Peters(University of Trieste), Astrid Petersmann(University of Cambridge), Julian Peto(University of Sassari), Paul D.P. Pharoah(University of Cambridge), Nicola Pirastu(University of Trieste), Ailith Pirie(Group Health Cooperative), Giorgio Pistis(University of Sassari), Ozren Polašek(Fondazione IRCCS Istituto Nazionale dei Tumori), David J. Porteous(Cedars-Sinai Medical Center), Bruce M. Psaty(Group Health Cooperative), Katri Pylkäs(NordLab), Paolo Radice(German Cancer Research Center), Leslie J. Raffel(Cedars-Sinai Medical Center), Fernando Rivadeneira(Erasmus MC), Igor Rudan(Institute of Genetic and Biomedical Research), Anja Rudolph(Guy's Hospital), Daniela Ruggiero(Institute on Aging), Cinzia Sala(The Netherlands Cancer Institute), Serena Sanna(Universitätsmedizin Greifswald), Elinor J. Sawyer(Guy's Hospital), David Schlessinger(Institute of Cancer Research), Marjanka K. Schmidt(University of Cambridge), Frank Schmidt(Universitätsmedizin Greifswald), Rita K. Schmutzler(Centre hospitalier universitaire de Québec), Minouk J. Schoemaker(Institute of Cancer Research), Robert A. Scott(The University of Melbourne), Caroline Seynaeve(Erasmus MC), Jacques Simard(Helmholtz Zentrum München), Rossella Sorice(Institute of Cancer Research), Melissa C. Southey(The University of Melbourne), Doris Stöckl(deCODE Genetics (Iceland)), Konstantin Strauch(Helmholtz Zentrum München), Anthony J. Swerdlow(Centre for Human Genetics), Kent D. Taylor(Université Paris-Sud), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Amanda E. Toland(Mayo Clinic), Ian M. Tomlinson(Centre for Human Genetics), Thérèse Truong(Université Paris-Sud), Laufey Tryggvadóttír(Icelandic Cancer Society), Stephen T. Turner(Mayo Clinic), Diego Vozzi(IRCCS Materno Infantile Burlo Garofolo), Qin Wang(University of Cambridge), Melissa Wellons(University Medical Center Groningen), Gonneke Willemsen(Institute of Genetics and Cancer), James F. Wilson(National Centre of Scientific Research "Demokritos"), Robert Winqvist(NordLab), Bruce H. R. Wolffenbuttel(University Medical Center Groningen), Alan F. Wright(Universitätsmedizin Greifswald), Drakoulis Yannoukakos(SIB Swiss Institute of Bioinformatics), Tatijana Zemunik(Vrije Universiteit Amsterdam), Wei Zheng(Brigham and Women's Hospital), Marek Zygmunt(Universitätsmedizin Greifswald), Sven Bergmann(SIB Swiss Institute of Bioinformatics), Dorret I. Boomsma(University of Iceland), Julie E. Buring(Brigham and Women's Hospital), Luigi Ferrucci(National Institute on Aging), Grant W. Montgomery(University Medical Center Groningen), Vilmundur Guðnason(University of Iceland), Tim D. Spector(King's College London), Cornelia M. van Duijn(University of Cambridge), Behrooz Z. Alizadeh(University Medical Center Groningen), Marina Ciullo(Helmholtz Zentrum München), Laura Crisponi(Institute of Genetic and Biomedical Research), Douglas F. Easton(University of Cambridge), Paolo Gasparini(University of Trieste), Christian Gieger(Harvard University), Tamara B. Harris(University of Washington), Caroline Hayward(Institute of Genetics and Cancer), Sharon L. R. Kardia(University of Michigan), Peter Kraft(Harvard University), Barbara McKnight(Brigham and Women's Hospital), Andres Metspalu(UCLA Medical Center), Alanna C. Morrison(The University of Texas Health Science Center at Houston), Alex P. Reiner(University of Washington), Paul M. Ridker(Brigham and Women's Hospital), Jerome I. Rotter(Universitätsmedizin Greifswald), Daniela Toniolo(University of Cambridge), André G. Uitterlinden(University of Michigan), Sheila Ulivi(University of Maryland, Baltimore), Henry Völzke(Harvard University), Nicholas J. Wareham(deCODE Genetics (Iceland)), David R. Weir(University of Michigan), Laura M. Yerges-Armstrong(University of Maryland, Baltimore), Alkes L. Price(Harvard University), Kāri Stefánsson(Boston University), Jenny A. Visser(University of Cambridge), Ken K. Ong(University of Exeter), Jenny Chang‐Claude(German Cancer Research Center), Joanne M. Murabito(Boston University), John R. B. Perry(University of Cambridge), Anna Murray(University of Exeter)
Cited by 450Open Access
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.
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