大规模基因组分析将生殖衰老与下丘脑信号传导、乳腺癌易感性及BRCA1介导的DNA修复联系起来。
Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.
作者信息
Day Felix R, Ruth Katherine S, Thompson Deborah J, Lunetta Kathryn L, Pervjakova Natalia, Chasman Daniel I, Stolk Lisette, Finucane Hilary K, Sulem Patrick, Bulik-Sullivan Brendan, Esko Tõnu, Johnson Andrew D, Elks Cathy E, Franceschini Nora, He Chunyan, Altmaier Elisabeth, Brody Jennifer A, Franke Lude L, Huffman Jennifer E, Keller Margaux F, McArdle Patrick F, Nutile Teresa, Porcu Eleonora, Robino Antonietta, Rose Lynda M, Schick Ursula M, Smith Jennifer A, Teumer Alexander, Traglia Michela, Vuckovic Dragana, Yao Jie, Zhao Wei, Albrecht Eva, Amin Najaf, Corre Tanguy, Hottenga Jouke-Jan, Mangino Massimo, Smith Albert V, Tanaka Toshiko, Abecasis Goncalo, Andrulis Irene L, Anton-Culver Hoda, Antoniou Antonis C, Arndt Volker, Arnold Alice M, Barbieri Caterina, Beckmann Matthias W, Beeghly-Fadiel Alicia, Benitez Javier, Bernstein Leslie, Bielinski Suzette J, Blomqvist Carl, Boerwinkle Eric, Bogdanova Natalia V, Bojesen Stig E, Bolla Manjeet K, Borresen-Dale Anne-Lise, Boutin Thibaud S, Brauch Hiltrud, Brenner Hermann, Brüning Thomas, Burwinkel Barbara, Campbell Archie, Campbell Harry, Chanock Stephen J, Chapman J Ross, Chen Yii-Der Ida, Chenevix-Trench Georgia, Couch Fergus J, Coviello Andrea D, Cox Angela, Czene Kamila, Darabi Hatef, De Vivo Immaculata, Demerath Ellen W, Dennis Joe, Devilee Peter, Dörk Thilo, Dos-Santos-Silva Isabel, Dunning Alison M, Eicher John D, Fasching Peter A, Faul Jessica D, Figueroa Jonine, Flesch-Janys Dieter, Gandin Ilaria, Garcia Melissa E, García-Closas Montserrat, Giles Graham G, Girotto Giorgia G, Goldberg Mark S, González-Neira Anna, Goodarzi Mark O, Grove Megan L, Gudbjartsson Daniel F, Guénel Pascal, Guo Xiuqing, Haiman Christopher A, Hall Per, Hamann Ute, Henderson Brian E, Hocking Lynne J, Hofman Albert, Homuth Georg, Hooning Maartje J, Hopper John L, Hu Frank B, Huang Jinyan, Humphreys Keith, Hunter David J, Jakubowska Anna, Jones Samuel E, Kabisch Maria, Karasik David, Knight Julia A, Kolcic Ivana, Kooperberg Charles, Kosma Veli-Matti, Kriebel Jennifer, Kristensen Vessela, Lambrechts Diether, Langenberg Claudia, Li Jingmei, Li Xin, Lindström Sara, Liu Yongmei, Luan Jian'an, Lubinski Jan, Mägi Reedik, Mannermaa Arto, Manz Judith, Margolin Sara, Marten Jonathan, Martin Nicholas G, Masciullo Corrado, Meindl Alfons, Michailidou Kyriaki, Mihailov Evelin, Milani Lili, Milne Roger L, Müller-Nurasyid Martina, Nalls Michael, Neale Ben M, Nevanlinna Heli, Neven Patrick, Newman Anne B, Nordestgaard Børge G, Olson Janet E, Padmanabhan Sandosh, Peterlongo Paolo, Peters Ulrike, Petersmann Astrid, Peto Julian, Pharoah Paul D P, Pirastu Nicola N, Pirie Ailith, Pistis Giorgio, Polasek Ozren, Porteous David, Psaty Bruce M, Pylkäs Katri, Radice Paolo, Raffel Leslie J, Rivadeneira Fernando, Rudan Igor, Rudolph Anja, Ruggiero Daniela, Sala Cinzia F, Sanna Serena, Sawyer Elinor J, Schlessinger David, Schmidt Marjanka K, Schmidt Frank, Schmutzler Rita K, Schoemaker Minouk J, Scott Robert A, Seynaeve Caroline M, Simard Jacques, Sorice Rossella, Southey Melissa C, Stöckl Doris, Strauch Konstantin, Swerdlow Anthony, Taylor Kent D, Thorsteinsdottir Unnur, Toland Amanda E, Tomlinson Ian, Truong Thérèse, Tryggvadottir Laufey, Turner Stephen T, Vozzi Diego, Wang Qin, Wellons Melissa, Willemsen Gonneke, Wilson James F, Winqvist Robert, Wolffenbuttel Bruce B H R, Wright Alan F, Yannoukakos Drakoulis, Zemunik Tatijana, Zheng Wei, Zygmunt Marek, Bergmann Sven, Boomsma Dorret I, Buring Julie E, Ferrucci Luigi, Montgomery Grant W, Gudnason Vilmundur, Spector Tim D, van Duijn Cornelia M, Alizadeh Behrooz Z, Ciullo Marina, Crisponi Laura, Easton Douglas F, Gasparini Paolo P, Gieger Christian, Harris Tamara B, Hayward Caroline, Kardia Sharon L R, Kraft Peter, McKnight Barbara, Metspalu Andres, Morrison Alanna C, Reiner Alex P, Ridker Paul M, Rotter Jerome I, Toniolo Daniela, Uitterlinden André G, Ulivi Sheila, Völzke Henry, Wareham Nicholas J, Weir David R, Yerges-Armstrong Laura M, Price Alkes L, Stefansson Kari, Visser Jenny A, Ong Ken K, Chang-Claude Jenny, Murabito Joanne M, Perry John R B, Murray Anna
机构信息
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
出版信息
Nat Genet. 2015 Nov;47(11):1294-1303. doi: 10.1038/ng.3412. Epub 2015 Sep 28.
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.
绝经时间对不孕症和包括乳腺癌在内的疾病风险有重大影响，但其潜在机制尚不清楚。我们对约7万名女性采用了一种双重策略，以识别与自然绝经年龄（ANM）相关的常见和低频蛋白质编码变异。我们确定了44个含有常见变异的区域，其中两个区域含有额外的具有重大影响的罕见错义等位基因。我们发现参与青春期延迟的基因内部或附近信号富集，这突出了生殖寿命开始和结束之间的首个分子联系。通路分析确定了与DNA损伤反应（DDR）基因的主要关联，包括BRCA1中首个与任何复杂性状相关的常见编码变异。孟德尔随机化分析支持了较晚的ANM对乳腺癌风险的因果效应（每年风险增加约6%；P = 3×10^(-14)），这可能是由延长的性激素暴露而非DDR机制介导的。
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