Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Lisette Stolk, John R.B. Perry, Daniel I. Chasman, Chunyan He, Massimo Mangino, Patrick Sulem, Maja Barbalic, Linda Broer, Enda M. Byrne, Florian Ernst, Tmu Esko, Nora Franceschini, Daniel F. Gudbjartsson, Jouke Jan Hottenga, Peter Kraft, Patrick F. McArdle, Eleonora Porcu, So Youn Shin, Albert V. Smith, Sophie Van WingerdenGuangju Zhai, Wei V. Zhuang, Eva Albrecht, Behrooz Z. Alizadeh, Thor Aspelund, Stefania Bandinelli, Lovorka Barac Lauc, Jacques S. Beckmann, Mladen Boban, Eric Boerwinkle, Frank J. Broekmans, Andrea Burri, Harry Campbell, Stephen J. Chanock, Constance Chen, Marilyn C. Cornelis, Tanguy Corre, Andrea D. Coviello, Pio D'Adamo, Gail Davies, Ulf De Faire, Eco J.C. De Geus, Ian J. Deary, George V.Z. Dedoussis, Panagiotis Deloukas, Shah Ebrahim, Gudny Eiriksdottir, Valur Emilsson, Johan G. Eriksson, Bart C.J.M. Fauser, Liana Ferreli, Luigi Ferrucci, Krista Fischer, Aaron R. Folsom, Melissa E. Garcia, Paolo Gasparini, Christian Gieger, Nicole Glazer, Diederick E. Grobbee, Per Hall, Toomas Haller, Susan E. Hankinson, Merli Hass, Caroline Hayward, Andrew C. Heath, Albert Hofman, Erik Ingelsson, A. Cecile J.W. Janssens, Andrew D. Johnson, David Karasik, Sharon L.R. Kardia, Jules Keyzer, Douglas P. Kiel, Ivana Kolcic, Zoltn Kutalik, Jari Lahti, Sandra Lai, Triin Laisk, Joop S.E. Laven, Debbie A. Lawlor, Jianjun Liu, Lorna M. Lopez, Yvonne V. Louwers, Patrik K.E. Magnusson, Mara Marongiu, Nicholas G. Martin, Irena Martinovic Klaric, Corrado Masciullo, Barbara McKnight, Sarah E. Medland, David Melzer, Vincent Mooser, Pau Navarro, Anne B. Newman, Dale R. Nyholt, N. Charlotte Onland-Moret, Aarno Palotie, Guillaume Paré, Alex N. Parker, Nancy L. Pedersen, Petra H.M. Peeters, Giorgio Pistis, Andrew S. Plump, Ozren Polasek, Victor J.M. Pop, Bruce M. Psaty, Katri R Currency Signikkönen, Emil Rehnberg, Jerome I. Rotter, Igor Rudan, Cinzia Sala, Andres Salumets, Angelo Scuteri, Andrew Singleton, Jennifer A. Smith, Harold Snieder, Nicole Soranzo, Simon N. Stacey, John M. Starr, Maria G. Stathopoulou, Kathleen Stirrups, Ronald P. Stolk, Unnur Styrkarsdottir, Yan V. Sun, Albert Tenesa, Barbara Thorand, Daniela Toniolo, Laufey Tryggvadottir, Kim Tsui, Sheila Ulivi, Rob M. Van Dam, Yvonne T. Van Der Schouw, Carla H. Van Gils, Peter Van Nierop, Jacqueline M. Vink, Peter M. Visscher, Marlies Voorhuis, Gérard Waeber, Henri Wallaschofski, H. Erich Wichmann, Elisabeth Widen, Colette J.M. Wijnands-Van Gent, Gonneke Willemsen, James F. Wilson, Bruce H.R. Wolffenbuttel, Alan F. Wright, Laura M. Yerges-Armstrong, Tatijana Zemunik, Lina Zgaga, M. Carola Zillikens, Marek Zygmunt, Alice M. Arnold, Dorret I. Boomsma, Julie E. Buring, Laura Crisponi, Ellen W. Demerath, Vilmundur Gudnason, Tamara B. Harris, Frank B. Hu, David J. Hunter, Lenore J. Launer, Andres Metspalu, Grant W. Montgomery, Ben A. Oostra, Paul M. Ridker, Serena Sanna, David Schlessinger, Tim D. Spector, Kari Stefansson, Elizabeth A. Streeten, Unnur Thorsteinsdottir, Manuela Uda, André G. Uitterlinden, Cornelia M. Van Duijn, Henry Völzke, Anna Murray, Joanne M. Murabito, Jenny A. Visser, Kathryn L. Lunetta

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Abstract

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 - 10 g8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-I °B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Original languageEnglish
Pages (from-to)260-268
Number of pages9
JournalNature Genetics
Volume44
Issue number3
DOIs
StatePublished - Mar 1 2012

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    Stolk, L., Perry, J. R. B., Chasman, D. I., He, C., Mangino, M., Sulem, P., Barbalic, M., Broer, L., Byrne, E. M., Ernst, F., Esko, T., Franceschini, N., Gudbjartsson, D. F., Hottenga, J. J., Kraft, P., McArdle, P. F., Porcu, E., Shin, S. Y., Smith, A. V., ... Lunetta, K. L. (2012). Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nature Genetics, 44(3), 260-268. https://doi.org/10.1038/ng.1051