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, 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, J Chapman, R, Chen, Y-DIda, 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'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, 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, 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
Pagination1294-1303
Date Published2015 Nov
ISSN1546-1718
KeywordsAdult, Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomics, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, 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
Alternate JournalNat Genet
PubMed ID26414677
PubMed Central IDPMC4661791
Grant ListR01HL59367 / HL / NHLBI NIH HHS / United States
R01DK075787 / DK / NIDDK NIH HHS / United States
16459 / CRUK_ / Cancer Research UK / United Kingdom
K01-HL116770 / HL / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
16563 / CRUK_ / Cancer Research UK / United Kingdom
10124 / CRUK_ / Cancer Research UK / United Kingdom
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
N01HC85080 / HC / NHLBI NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
N.1-AG-1-2111 / AG / NIA NIH HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
N01-AG-1-2109 / AG / NIA NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL087660 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01AG62101 / AG / NIA NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
HHSN271201100004C / AG / NIA NIH HHS / United States
C12292/A11174 / CRUK_ / Cancer Research UK / United Kingdom
N01-HC-95159 / HC / NHLBI NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
1U19 CA148065 / CA / NCI NIH HHS / United States
C5047/A10692 / CRUK_ / Cancer Research UK / United Kingdom
HHSN271201100005C / DA / NIDA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
1U19 CA148537 / CA / NCI NIH HHS / United States
11174 / CRUK_ / Cancer Research UK / United Kingdom
UL1 TR001108 / TR / NCATS NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
17528 / CRUK_ / Cancer Research UK / United Kingdom
C5047/A8384 / CRUK_ / Cancer Research UK / United Kingdom
MC_UU_12015/2 / MRC_ / Medical Research Council / United Kingdom
N01HC85081 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
C1287/A 10710 / CRUK_ / Cancer Research UK / United Kingdom
CZD/16/6/4 / CSO_ / Chief Scientist Office / United Kingdom
CA164920 / CA / NCI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HL054464 / HL / NHLBI NIH HHS / United States
N.1-AG-1-1 / AG / NIA NIH HHS / United States
HL087660 / HL / NHLBI NIH HHS / United States
16565 / CRUK_ / Cancer Research UK / United Kingdom
RC2 AG036495 / AG / NIA NIH HHS / United States
HG006513 / HG / NHGRI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
C5047/A15007 / CRUK_ / Cancer Research UK / United Kingdom
MC_U106179472 / MRC_ / Medical Research Council / United Kingdom
16561 / CRUK_ / Cancer Research UK / United Kingdom
N01-HC-95160 / HC / NHLBI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
090532 / WT_ / Wellcome Trust / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
U01-HL84756 / HL / NHLBI NIH HHS / United States
HL054457 / HL / NHLBI NIH HHS / United States
U01AG009740 / AG / NIA NIH HHS / United States
AG009740 / AG / NIA NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
1U19 CA148112 / CA / NCI NIH HHS / United States
HG005552 / HG / NHGRI NIH HHS / United States
HL080467 / HL / NHLBI NIH HHS / United States
HG007022 / HG / NHGRI NIH HHS / United States
R21 AG032598 / AG / NIA NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
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HL080295 / HL / NHLBI NIH HHS / United States
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N01AG62106 / AG / NIA NIH HHS / United States
HG005581 / HG / NHGRI NIH HHS / United States
C1281/A12014 / CRUK_ / Cancer Research UK / United Kingdom
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
R21AG032598 / AG / NIA NIH HHS / United States
R01AG29451 / AG / NIA NIH HHS / United States
C8197/A16565 / CRUK_ / Cancer Research UK / United Kingdom
UM1 CA182910 / CA / NCI NIH HHS / United States
C1287/A10118 / CRUK_ / Cancer Research UK / United Kingdom
AG023629 / AG / NIA NIH HHS / United States
15007 / CRUK_ / Cancer Research UK / United Kingdom
MC_U106179471 / MRC_ / Medical Research Council / United Kingdom
U01-HL72515 / HL / NHLBI NIH HHS / United States
N01-AG-5-0002 / AG / NIA NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HG007089 / HG / NHGRI NIH HHS / United States
10119 / CRUK_ / Cancer Research UK / United Kingdom

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