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

dc.contributor.authorDay, Felix R.
dc.contributor.authorRuth, Katherine S.
dc.contributor.authorThompson, Deborah J.
dc.contributor.authorLunetta, Kathryn L.
dc.contributor.authorPervjakova, Natalia
dc.contributor.authorChasman, Daniel I.
dc.contributor.authorStolk, Lisette
dc.contributor.authorFinucane, Hilary K.
dc.contributor.authorSulem, Patrick
dc.contributor.authorBulik-Sullivan, Brendan
dc.contributor.authorEsko, Tõnu
dc.contributor.authorJohnson, Andrew D.
dc.contributor.authorElks, Cathy E.
dc.contributor.authorFranceschini, Nora
dc.contributor.authorHe, Chunyan
dc.contributor.authorAltmaier, Elisabeth
dc.contributor.authorBrody, Jennifer A.
dc.contributor.authorFranke, Lude L.
dc.contributor.authorHuffman, Jennifer E.
dc.contributor.authorKeller, Margaux F.
dc.contributor.authorMcArdle, Patrick F.
dc.contributor.authorNutile, Teresa
dc.contributor.authorPorcu, Eleonora
dc.contributor.authorRobino, Antonietta
dc.contributor.authorRose, Lynda M.
dc.contributor.authorSchick, Ursula M.
dc.contributor.authorSmith, Jennifer A.
dc.contributor.authorTeumer, Alexander
dc.contributor.authorTraglia, Michela
dc.contributor.authorVuckovic, Dragana
dc.contributor.authorYao, Jie
dc.contributor.authorZhao, Wei
dc.contributor.authorAlbrecht, Eva
dc.contributor.authorAmin, Najaf
dc.contributor.authorCorre, Tanguy
dc.contributor.authorHottenga, Jouke-Jan
dc.contributor.authorMangino, Massimo
dc.contributor.authorSmith, Albert V.
dc.contributor.authorTanaka, Toshiko
dc.contributor.authorAbecasis, Goncalo
dc.contributor.authorAndrulis, Irene L.
dc.contributor.authorAnton-Culver, Hoda
dc.contributor.authorAntoniou, Antonis C.
dc.contributor.authorArndt, Volker
dc.contributor.authorArnold, Alice M.
dc.contributor.authorBarbieri, Caterina
dc.contributor.authorBeckmann, Matthias W.
dc.contributor.authorBeeghly-Fadiel, Alicia
dc.contributor.authorBenitez, Javier
dc.contributor.authorBernstein, Leslie
dc.contributor.authorBielinski, Suzette J.
dc.contributor.authorBlomqvist, Carl
dc.contributor.authorBoerwinkle, Eric
dc.contributor.authorBogdanova, Natalia V.
dc.contributor.authorBojesen, Stig E.
dc.contributor.authorBolla, Manjeet K.
dc.contributor.authorBorresen-Dale, Anne-Lise
dc.contributor.authorBoutin, Thibaud S.
dc.contributor.authorBrauch, Hiltrud
dc.contributor.authorBrenner, Hermann
dc.contributor.authorBrüning, Thomas
dc.contributor.authorBurwinkel, Barbara
dc.contributor.authorCampbell, Archie
dc.contributor.authorCampbell, Harry
dc.contributor.authorChanock, Stephen J.
dc.contributor.authorChapman, J. Ross
dc.contributor.authorChen, Yii-Der Ida
dc.contributor.authorChenevix-Trench, Georgia
dc.contributor.authorCouch, Fergus J.
dc.contributor.authorCoviello, Andrea D.
dc.contributor.authorCox, Angela
dc.contributor.authorCzene, Kamila
dc.contributor.authorDarabi, Hatef
dc.contributor.authorDe Vivo, Immaculata
dc.contributor.authorDemerath, Ellen W.
dc.contributor.authorDennis, Joe
dc.contributor.authorDevilee, Peter
dc.contributor.authorDörk, Thilo
dc.contributor.authordos-Santos-Silva, Isabel
dc.contributor.authorDunning, Alison M.
dc.contributor.authorEicher, John D.
dc.contributor.authorFasching, Peter A.
dc.contributor.authorFaul, Jessica D.
dc.contributor.authorFigueroa, Jonine
dc.contributor.authorFlesch-Janys, Dieter
dc.contributor.authorGandin, Ilaria
dc.contributor.authorGarcia, Melissa E.
dc.contributor.authorGarcía-Closas, Montserrat
dc.contributor.authorGiles, Graham G.
dc.contributor.authorGirotto, Giorgia G.
dc.contributor.authorGoldberg, Mark S.
dc.contributor.authorGonzález-Neira, Anna
dc.contributor.authorGoodarzi, Mark O.
dc.contributor.authorGrove, Megan L.
dc.contributor.authorGudbjartsson, Daniel F.
dc.contributor.authorGuénel, Pascal
dc.contributor.authorGuo, Xiuqing
dc.contributor.authorHaiman, Christopher A.
dc.contributor.authorHall, Per
dc.contributor.authorHamann, Ute
dc.contributor.authorHenderson, Brian E.
dc.contributor.authorHocking, Lynne J.
dc.contributor.authorHofman, Albert
dc.contributor.authorHomuth, Georg
dc.contributor.authorHooning, Maartje J.
dc.contributor.authorHopper, John L.
dc.contributor.authorHu, Frank B.
dc.contributor.authorHuang, Jinyan
dc.contributor.authorHumphreys, Keith
dc.contributor.authorHunter, David J.
dc.contributor.authorJakubowska, Anna
dc.contributor.authorJones, Samuel E.
dc.contributor.authorKabisch, Maria
dc.contributor.authorKarasia, David
dc.contributor.authorKnight, Julia A.
dc.contributor.authorKolcic, Ivana
dc.contributor.authorKooperberg, Charles
dc.contributor.authorKosma, Veli-Matti
dc.contributor.authorKriebel, Jennifer
dc.contributor.authorKristensen, Vessela
dc.contributor.authorLambrechts, Diether
dc.contributor.authorLangenberg, Claudia
dc.contributor.authorLi, Jingmei
dc.contributor.authorLi, Xin
dc.contributor.authorLindström, Sara
dc.contributor.authorLiu, Yongmei
dc.contributor.authorLuan, Jian’an
dc.contributor.authorLubinski, Jan
dc.contributor.authorMägi, Reedik
dc.contributor.authorMannermaa, Arto
dc.contributor.authorManz, Judith
dc.contributor.authorMargolin, Sara
dc.contributor.authorMarten, Jonathan
dc.contributor.authorMartin, Nicholas G.
dc.contributor.authorMasciullo, Corrado
dc.contributor.authorMeindl, Alfons
dc.contributor.authorMichailidou, Kyriaki
dc.contributor.authorMihailov, Evelin
dc.contributor.authorMilani, Lili
dc.contributor.authorMilne, Roger L.
dc.contributor.authorMüller-Nurasyid, Martina
dc.contributor.authorNalls, Michael
dc.contributor.authorNeale, Ben M.
dc.contributor.authorNevanlinna, Heli
dc.contributor.authorNeven, Patrick
dc.contributor.authorNewman, Anne B.
dc.contributor.authorNordestgaard, Børge G.
dc.contributor.authorOlson, Janet E.
dc.contributor.authorPadmanabhan, Sandosh
dc.contributor.authorPeterlongo, Paolo
dc.contributor.authorPeters, Ulrike
dc.contributor.authorPetersmann, Astrid
dc.contributor.authorPeto, Julian
dc.contributor.authorPharoah, Paul D.P.
dc.contributor.authorPirastu, Nicola N.
dc.contributor.authorPirie, Ailith
dc.contributor.authorPistis, Giorgio
dc.contributor.authorPolasek, Ozren
dc.contributor.authorPorteous, David
dc.contributor.authorPsaty, Bruce M.
dc.contributor.authorPylkäs, Katri
dc.contributor.authorRadice, Paolo
dc.contributor.authorRaffel, Leslie J.
dc.contributor.authorRivadeneira, Fernando
dc.contributor.authorRudan, Igor
dc.contributor.authorRudolph, Anja
dc.contributor.authorAnja, Daniela
dc.contributor.authorSala, Cinzia F.
dc.contributor.authorSanna, Serena
dc.contributor.authorSawyer, Elinor J.
dc.contributor.authorSchlessinger, David
dc.contributor.authorSchmidt, Marjanka K.
dc.contributor.authorSchmidt, Frank
dc.contributor.authorSchmutzler, Rita K.
dc.contributor.authorSchoemaker, Minouk J.
dc.contributor.authorScott, Robert A.
dc.contributor.authorSeynaeve, Caroline M.
dc.contributor.authorSimard, Jacques
dc.contributor.authorSorice, Rossella
dc.contributor.authorSouthey, Melissa C.
dc.contributor.authorStöckl, Doris
dc.contributor.authorStrauch, Konstantin
dc.contributor.authorSwerdlow, Anthony
dc.contributor.authorTaylor, Kent D.
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorToland, Amanda E.
dc.contributor.authorTomlinson, Ian
dc.contributor.authorTruong, Thérèse
dc.contributor.authorTryggvadottir, Laufey
dc.contributor.authorTurner, Stephen T.
dc.contributor.authorVozzi, Diego
dc.contributor.authorWang, Qin
dc.contributor.authorWellons, Melissa
dc.contributor.authorWillemsen, Gonneke
dc.contributor.authorWilson, James F.
dc.contributor.authorWinqvist, Robert
dc.contributor.authorWolffenbuttel, Bruce B.H.R.
dc.contributor.authorWright, Alan F.
dc.contributor.authorYannoukakos, Drakoulis
dc.contributor.authorZemunik, Tatijana
dc.contributor.authorZheng, Wei
dc.contributor.authorZygmunt, Marek
dc.contributor.authorBergmann, Sven
dc.contributor.authorBoomsma, Dorret I.
dc.contributor.authorBuring, Julie E.
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorMontgomery, Grant W.
dc.contributor.authorGudnason, Vilmundur
dc.contributor.authorSpector, Tim D.
dc.contributor.authorvan Duijn, Cornelia M
dc.contributor.authorAlizadeh, Behrooz Z.
dc.contributor.authorCiullo, Marina
dc.contributor.authorCrisponi, Laura
dc.contributor.authorEaston, Douglas F.
dc.contributor.authorGasparini, Paolo P.
dc.contributor.authorGieger, Christian
dc.contributor.authorHarris, Tamara B.
dc.contributor.authorHayward, Caroline
dc.contributor.authorKardia, Sharon L.R.
dc.contributor.authorKraft, Peter
dc.contributor.authorMcKnight, Barbara
dc.contributor.authorMetspalu, Andres
dc.contributor.authorMorrison, Alanna C.
dc.contributor.authorReiner, Alex P.
dc.contributor.authorRidker, Paul M.
dc.contributor.authorRotter, Jerome I.
dc.contributor.authorToniolo, Daniela
dc.contributor.authorUitterlinden, André G.
dc.contributor.authorUlivi, Sheila
dc.contributor.authorVölzke, Henry
dc.contributor.authorWareham, Nicholas J.
dc.contributor.authorWeir, David R.
dc.contributor.authorYerges-Armstrong, Laura M.
dc.contributor.authorPrice, Alkes L.
dc.contributor.authorStefansson, Kari
dc.contributor.authorVisser, Jenny A.
dc.contributor.authorOng, Ken K.
dc.contributor.authorChang-Claude, Jenny
dc.contributor.authorMurabito, Joanne M.
dc.contributor.authorPerry, John R.B.
dc.contributor.authorMurray, Anna
dc.contributor.departmentDepartment of Epidemiology, Richard M. Fairbanks School of Public Healthen_US
dc.date.accessioned2017-07-11T19:38:17Z
dc.date.available2017-07-11T19:38:17Z
dc.date.issued2015-11
dc.description.abstractMenopause 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.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationDay, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., … Murray, A. (2015). Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), 1294–1303. http://doi.org/10.1038/ng.3412en_US
dc.identifier.urihttps://hdl.handle.net/1805/13400
dc.language.isoen_USen_US
dc.publisherSpringerNatureen_US
dc.relation.isversionof10.1038/ng.3412en_US
dc.relation.journalNature Geneticsen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectBRCA1 Proteinen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectGene Regulatory Networksen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectGenomicsen_US
dc.subjectHypothalamusen_US
dc.subjectMenopauseen_US
dc.subjectReproductionen_US
dc.subjectSignal Transductionen_US
dc.titleLarge-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repairen_US
dc.typeArticleen_US
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