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Title: Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
Authors: Day FR,  Ruth KS,  Thompson DJ,  Lunetta KL,  Pervjakova N,  Chasman DI,  Stolk L,  Finucane HK,  Sulem P,  Bulik-Sullivan B,  Esko T,  Johnson AD,  Elks CE,  Franceschini N,  He C,  Altmaier E,  Brody JA,  Franke LL,  Huffman JE,  Keller MF,  McArdle PF,  Nutile T,  Porcu E,  Robino A,  Rose LM,  Schick UM,  Smith JA,  Teumer A,  Traglia M,  Vuckovic D,  Yao J,  Zhao W,  Albrecht E,  Amin N,  Corre T,  Hottenga JJ,  Mangino M,  Smith AV,  Tanaka T,  Abecasis GR,  Andrulis IL,  Anton-Culver H,  Antoniou AC,  Arndt V,  Arnold AM,  Barbieri C,  Beckmann MW,  Beeghly-Fadiel A,  Benitez J,  Bernstein L,  Bielinski SJ,  Blomqvist C,  Boerwinkle E,  Bogdanova NV,  Bojesen SE,  Bolla MK,  Borresen-Dale AL,  Boutin TS,  Brauch H,  Brenner H,  Brüning T,  Burwinkel B,  Campbell A,  Campbell H,  Chanock SJ,  Chapman JR,  Chen YD,  Chenevix-Trench G,  Couch FJ,  Coviello AD,  Cox A,  Czene K,  Darabi H,  De Vivo I,  Demerath EW,  Dennis J,  Devilee P,  Dörk T,  Dos-Santos-Silva I,  Dunning AM,  Eicher JD,  Fasching PA,  Faul JD,  Figueroa J,  Flesch-Janys D,  Gandin I,  Garcia ME,  García-Closas M,  Giles GG,  Girotto GG,  Goldberg MS,  González-Neira A,  Goodarzi MO,  Grove ML,  Gudbjartsson DF,  Guénel P,  Guo X,  Haiman CA,  Hall P,  Hamann U,  Henderson BE,  Hocking LJ,  Hofman A,  Homuth G,  Hooning MJ,  Hopper JL,  Hu FB,  Huang J,  Humphreys K,  Hunter DJ,  Jakubowska A,  Jones SE,  Kabisch M,  Karasik D,  Knight JA,  Kolcic I,  Kooperberg C,  Kosma VM,  Kriebel J,  Kristensen V,  Lambrechts D,  Langenberg C,  Li J,  Li X,  Lindström S,  Liu Y,  Luan J,  Lubinski J,  Mägi R,  Mannermaa A,  Manz J,  Margolin S,  Marten J,  Martin NG,  Masciullo C,  Meindl A,  Michailidou K,  Mihailov E,  Milani L,  Milne RL,  Müller-Nurasyid M,  Nalls M,  Neale BM,  Nevanlinna H,  Neven P,  Newman AB,  Nordestgaard BG,  Olson JE,  Padmanabhan S,  Peterlongo P,  Peters U,  Petersmann A,  Peto J,  Pharoah PD,  Pirastu NN,  Pirie A,  Pistis G,  Polasek O,  Porteous D,  Psaty BM,  Pylkäs K,  Radice P,  Raffel LJ,  Rivadeneira F,  Rudan I,  Rudolph A,  Ruggiero D,  Sala CF,  Sanna S,  Sawyer EJ,  Schlessinger D,  Schmidt MK,  Schmidt F,  Schmutzler RK,  Schoemaker MJ,  Scott RA,  Seynaeve CM,  Simard J,  Sorice R,  Southey MC,  Stöckl D,  Strauch K,  Swerdlow A,  Taylor KD,  Thorsteinsdottir U,  Toland AE,  Tomlinson I,  Truong T,  Tryggvadottir L,  Turner ST,  Vozzi D,  Wang Q,  Wellons M,  Willemsen G,  Wilson JF,  Winqvist R,  Wolffenbuttel BB,  Wright AF,  Yannoukakos D,  Zemunik T,  Zheng W,  Zygmunt M,  Bergmann S,  Boomsma DI,  Buring JE,  Ferrucci L,  Montgomery GW,  Gudnason V,  Spector TD,  van Duijn CM,  Alizadeh BZ,  Ciullo M,  Crisponi L,  Easton DF,  Gasparini PP,  Gieger C,  Harris TB,  Hayward C,  Kardia SL,  Kraft P,  McKnight B,  Metspalu A,  Morrison AC,  Reiner AP,  Ridker PM,  Rotter JI,  Toniolo D,  Uitterlinden AG,  Ulivi S,  Völzke H,  Wareham NJ,  Weir DR,  Yerges-Armstrong LM,  PRACTICAL Consortium,  kConFab Investigators,  AOCS Investigators,  Generation Scotland,  EPIC-InterAct Consortium,  LifeLines Cohort Study,  Price AL,  Stefansson K,  Visser JA,  Ong KK,  Chang-Claude J,  Murabito JM,  Perry JR,  Murray A
Journal: Nat Genet
Date: 2015 Nov
Branches: LGS, MEB, OD
PubMed ID: 26414677
PMC ID: PMC4661791
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.