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

• Published in: Nature genetics Vol. 47; no. 11; pp. 1294 - 1303
• Main Authors: Thompson, Deborah J, Pervjakova, Natalia, Chasman, Daniel I, Esko, Tõnu, Elks, Cathy E, He, Chunyan, Altmaier, Elisabeth, Huffman, Jennifer E, Keller, Margaux F, McArdle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Corre, Tanguy, Smith, Albert V, Antoniou, Antonis C, Barbieri, Caterina, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Borresen-Dale, Anne-Lise, Chapman, J Ross, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Demerath, Ellen W, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Garcia, Melissa E, Girotto, Giorgia G, Goldberg, Mark S, Gudbjartsson, Daniel F, Haiman, Christopher A, Homuth, Georg, Hu, Frank B, Hunter, David J, Jakubowska, Anna, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Langenberg, Claudia, Liu, Yongmei, Luan, Jian'an, Manz, Judith, Masciullo, Corrado, Milani, Lili, Milne, Roger L, Müller-Nurasyid, Martina, Neale, Benjamin M, Neven, Patrick, Newman, Anne B, Nordestgaard, Børge G, Padmanabhan, Sandosh, Peters, Ulrike, Peto, Julian, Pirie, Ailith, Pistis, Giorgio, Porteous, David, Psaty, Bruce M, Pylkäs, Katri, Radice, Paolo, Rivadeneira, Fernando, Rudan, Igor, Sawyer, Elinor J, Schlessinger, David, Schmidt, Marjanka K, Schmidt, Frank, Seynaeve, Caroline M, Simard, Jacques, Southey, Melissa C, Stöckl, Doris, Strauch, Konstantin, Toland, Amanda E, Tomlinson, Ian, Tryggvadottir, Laufey, Turner, Stephen T, Willemsen, Gonneke, Wright, Alan F, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I, Montgomery, Grant W, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Crisponi, Laura, Easton, Douglas F, Harris, Tamara B, Kraft, Peter, McKnight, Barbara, Rotter, Jerome I, Ulivi, Sheila, Wareham, Nicholas J, Yerges-Armstrong, Laura M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2015; Nature Publishing Group
• Subjects: 45; 45/43; 631/208/205/2138; 692/699/67/1347; Adult; Age Factors; Aging - genetics; Agriculture; Animal Genetics and Genomics; Biomedicine; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - genetics; Cancer Research; Cellular signal transduction; Consortia; Deoxyribonucleic acid; Development and progression; Disease susceptibility; DNA; DNA Repair; Female; Gene Function; Gene Regulatory Networks - genetics; Genealogy; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome-Wide Association Study - methods; Genomes; Genomics - methods; Genotype; Health aspects; Health risks; Human Genetics; Humans; Hypothalamus - metabolism; Identification and classification; Infertility; Menopause; Menopause - genetics; Meta-analysis; Middle Aged; Models, Genetic; Phenotype; Reproduction - genetics; Signal Transduction - genetics; Studies; Womens health
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3412

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response. 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.