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

TitleLarge-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
Publication TypeJournal Article
Year of Publication2015
AuthorsDay, 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, AVernon, 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, J Chapman, R, Chen, Y-DI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, De Vivo, I, Demerath, EW, Dennis, JG, 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, G, 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'an, 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, MA, 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, C, 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, K, 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, Zhang, 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, P, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, A, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, AG, Ulivi, S, Völzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, L, Price, AL, Stefansson, K, Visser, JA, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB, Murray, A
Corporate AuthorsPRACTICAL Consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study
JournalNat Genet
Volume47
Issue11
Pagination1294-303
Date Published2015 Nov
ISSN Number1546-1718
KeywordsAge Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Genome, Genome-Wide Association Study, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Older Adults, Phenotype, Reproduction, Signal Transduction
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.

DOI10.1038/ng.3412
User Guide Notes

http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract

Alternate JournalNat. Genet.
Citation Key8889
PubMed ID26414677
PubMed Central IDPMC4661791
Grant ListN01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
CA128978 / CA / NCI NIH HHS / United States
HL054481 / HL / NHLBI NIH HHS / United States
HL043851 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
P30-DK072488 / DK / NIDDK NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
N.1-AG-1-2111 / AG / NIA NIH HHS / United States
C5047/A10692 / / Cancer Research UK / United Kingdom
HHSN271201100004C / / PHS HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
11174 / / Cancer Research UK / United Kingdom
N01-AG-1-2109 / AG / NIA NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
HHSN268201100001C / / PHS HHS / United States
R01-088119 / / PHS HHS / United States
HHSN268201100005C / / PHS HHS / United States
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HL105756 / HL / NHLBI NIH HHS / United States
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1U19 CA148065 / CA / NCI NIH HHS / United States
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HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
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UL1 TR001108 / TR / NCATS NIH HHS / United States
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HHSN268200960009C / / PHS HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
R01 HL119443 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
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MC_U106179471 / / Medical Research Council / United Kingdom
C5047/A8384 / / Cancer Research UK / United Kingdom
HHSN268201100004C / / PHS HHS / United States
C12292/A11174 / / Cancer Research UK / United Kingdom
N01HC85081 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
MC_UU_12015/2 / / Medical Research Council / United Kingdom
CA164920 / CA / NCI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
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MC_U106179472 / / Medical Research Council / United Kingdom
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HL054464 / HL / NHLBI NIH HHS / United States
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C8197/A16565 / / Cancer Research UK / United Kingdom
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090532 / / Wellcome Trust / United Kingdom
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CZD/16/6/4 / / Chief Scientist Office / United Kingdom
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