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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited 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, J-J; Mangino, M; Smith, AV; Tanaka, T; Abecasis, G; 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, A-L; Boutin, TS; Brauch, H; Brenner, H; Brüning, T; Burwinkel, B; Campbell, A; Campbell, H; Chanock, SJ; Chapman, JR; Chen, Y-DI; 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, V-M; 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, PDP; 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, BBHR; 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, SLR; 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, JRB; Murray, A

Published Date

  • November 2015

Published In

Volume / Issue

  • 47 / 11

Start / End Page

  • 1294 - 1303

PubMed ID

  • 26414677

Pubmed Central ID

  • PMC4661791

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.3412

Language

  • eng

Conference Location

  • United States