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

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...

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Vydáno v:	Nature genetics Ročník 47; číslo 11; s. 1294 - 1303
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.11.2015 Nature Publishing Group
Témata:	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
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Shrnutí:	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.
Bibliografie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 These authors jointly supervised this work
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3412