@article {8889,
	title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.},
	journal = {Nat Genet},
	volume = {47},
	year = {2015},
	month = {2015 Nov},
	pages = {1294-303},
	abstract = {<p>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 {\texttimes} 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.</p>},
	keywords = {Age 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},
	issn = {1546-1718},
	doi = {10.1038/ng.3412},
	author = {Day, Felix R and Ruth, Katherine S and Thompson, Deborah J and Kathryn L Lunetta and Pervjakova, Natalia and Daniel I Chasman and Stolk, Lisette and Finucane, Hilary K and Sulem, Patrick and Bulik-Sullivan, Brendan and T{\~o}nu Esko and Andrew D Johnson and Elks, Cathy E and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A and Lude L Franke and Huffman, Jennifer E and Keller, Margaux F and McArdle, Patrick F and Nutile, Teresa and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M and Schick, Ursula M and Jennifer A Smith and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Wei Zhao and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Jouke-Jan Hottenga and Mangino, Massimo and Albert Vernon Smith and Toshiko Tanaka and Gon{\c c}alo R Abecasis and Andrulis, Irene L and Anton-Culver, Hoda and Antoniou, Antonis C and Arndt, Volker and Alice M. Arnold and Barbieri, Caterina and Beckmann, Matthias W and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V and Bojesen, Stig E and Manjeet K. Bolla and Borresen-Dale, Anne-Lise and Boutin, Thibaud S and Brauch, Hiltrud and Brenner, Hermann and Br{\"u}ning, Thomas and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J and Chapman, J Ross and Yii-Der I Chen and Chenevix-Trench, Georgia and Couch, Fergus J and Coviello, Andrea D and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Ellen W Demerath and Joe G Dennis and Devilee, Peter and D{\"o}rk, Thilo and Dos-Santos-Silva, Isabel and Dunning, Alison M and John D Eicher and Fasching, Peter A and Jessica Faul and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Melissa E Garcia and Garc{\'\i}a-Closas, Montserrat and Giles, Graham G and Giorgia G Girotto and Goldberg, Mark S and Gonz{\'a}lez-Neira, Anna and Goodarzi, Mark O and Grove, Megan L and Gudbjartsson, Daniel F and Gu{\'e}nel, Pascal and Guo, Xiuqing and Christopher A Haiman and Hall, Per and Hamann, Ute and Henderson, Brian E and Lynne J Hocking and Hofman, Albert and Homuth, Georg and Hooning, Maartje J and John L Hopper and Hu, Frank B and Huang, Jinyan and Humphreys, Keith and Hunter, David J and Jakubowska, Anna and Jones, Samuel E and Kabisch, Maria and Karasik, David and Knight, Julia A and Kolcic, Ivana and Charles Kooperberg and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindstr{\"o}m, Sara and Yongmei Liu and Luan, Jian{\textquoteright}an and Lubinski, Jan and M{\"a}gi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Nicholas G Martin and Masciullo, Corrado and Meindl, Alfons and Michailidou, Kyriaki and Mihailov, Evelin and Lili Milani and Milne, Roger L and M{\"u}ller-Nurasyid, Martina and Michael A Nalls and Neale, Benjamin M and Nevanlinna, Heli and Neven, Patrick and Anne B Newman and B{\o}rge G Nordestgaard and Olson, Janet E and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D P and Nicola Pirastu and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and David J Porteous and Psaty, Bruce M and Pylk{\"a}s, Katri and Radice, Paolo and Raffel, Leslie J and Fernando Rivadeneira and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Cinzia Felicita Sala and Sanna, Serena and Sawyer, Elinor J and Schlessinger, David and Schmidt, Marjanka K and Schmidt, Frank and Schmutzler, Rita K and Schoemaker, Minouk J and Scott, Robert A and Seynaeve, Caroline M and Simard, Jacques and Sorice, Rossella and Southey, Melissa C and St{\"o}ckl, Doris and Strauch, Konstantin and Swerdlow, Anthony and Kent D Taylor and Thorsteinsdottir, Unnur and Toland, Amanda E and Tomlinson, Ian and Truong, Th{\'e}r{\`e}se and Tryggvadottir, Laufey and Stephen T Turner and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Gonneke Willemsen and James F Wilson and Winqvist, Robert and Wolffenbuttel, Bruce B H R and Alan F Wright and Yannoukakos, Drakoulis and Zemunik, Tatijana and Wei Zhang and Zygmunt, Marek and Bergmann, Sven and Dorret I Boomsma and Buring, Julie E and Luigi Ferrucci and Grant W Montgomery and Gudnason, Vilmundur and Timothy Spector and Cornelia M van Duijn and Alizadeh, Behrooz Z and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F and Paolo P. Gasparini and Gieger, Christian and Tamara B Harris and Caroline Hayward and Sharon L R Kardia and Kraft, Peter and McKnight, Barbara and Andres Metspalu and Alanna C Morrison and Reiner, Alex P and Ridker, Paul M and Rotter, Jerome I and Toniolo, Daniela and Andr{\'e} G Uitterlinden and Ulivi, Sheila and V{\"o}lzke, Henry and Wareham, Nicholas J and David R Weir and Laura M Yerges-Armstrong and Price, Alkes L and Stefansson, Kari and Visser, Jenny A and Ong, Ken K and Chang-Claude, Jenny and Joanne M Murabito and Perry, John R B and Murray, Anna}
}
