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

Authors: Lisette Stolk, John R. B. Perry, Daniel I. Chasman, Chanyi He, Massimo Mangino, Patrick Sulem, Maja Barbalić, Linda Broer, Enda M. Byrne, Florian Ernst, Tõnu Esko, Nora Franceschini, Daníel F. Guðbjartsson, J-J Hottenga, Peter Kraft, Patrick F. McArdle, E. Porcu, Sohyeon Shin, Albert V. Smith, S. van Wingerden, Guijin Zhai, Wei Zhuang, Eva Albrecht, Behrooz Z. Alizadeh, Thor Aspelund, Stefania Bandinelli, Lovorka Barać Lauc, J. Beckmann, Mladen Boban, Eric Boerwinkle, Frank J. Broekmans, Andrea Burri, Harry Campbell, Stephen J. Chanock, C. Chen, Marilyn C. Cornelis, Tanguy Corre, Andrea D. Coviello, Pio D’Adamo, Gareth E. Davies, Ulf dé Fairé, Eco J. C. de Geus, Ian J. Deary, George Dedoussis, Panos Deloukas, Shah Ebrahim, G. Eiríksdóttir, Valur Emilsson, Johan G. Eriksson, Bart C.J.M. Fauser, Liana Ferreli, Luigi Ferrucci, Krista Fischer, Aaron R. Folsom, M. E. Garcia, Paolo Gasparini, Christian Gieger, Nicole L. Glazer, D. E. Grobbee, Per Hall, Toomas Haller, S. E. Hankinson, Merli Hass, Caroline Hayward, Andrew C. Heath, Albert Hofman, Erik Ingelsson, A. Cecile J.W. Janssens, Austin Johnson, David Karasik, Sharon L. R. Kardia, Jules J. Keyzer, Douglas P. Kiel, Ivana Kolčić, Zoltán Kutalik, Jari Lahti, Sandra Lai, Triin Laisk, Joop S.E. Laven, Debbie A. Lawlor, J. Liu, Lorna M. Lopez, Yvonne V. Louwers, Páll Magnússon, Mara Marongiu, Nicholas G. Martin, Irena Martinović Klarić, 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, Alexander N. Parker, Nancy L. Pedersen, P. H. M. Peeters, Giorgio Pistis, Andrew Plump, Ozren Polašek, Victor J.M. Pop, Bruce M. Psaty, Katri Räikkönen, Emil Rehnberg, Jerome I. Rotter, Igor Rudan, Cinzia Sala, Andres Salumets, Angelo Scuteri, Andy Singleton, Jennifer A. Smith, Harold Snieder, Nicole Soranzo, Simon Stacey, J.M. Starr, Maria G. Stathopoulou, Kathleen Stirrups, Ronald P. Stolk, Unnur Styrkársdóttir, Yan V. Sun, Albert Tenesa, Barbara Thorand, Daniela Toniolo, Laufey Tryggvadóttír, Kim Tsui, Sheila Ulivi, Rob M. van Dam, Yvonne T. van der Schouw, Carla H. van Gils, Pim van Nierop, Jacqueline M. Vink, Peter M. Visscher, Marlies Voorhuis, Gérard Waeber, Henri Wallaschofski, H-Erich Wichmann, Elisabeth Widén, C.J. Wijnands-van Gent, Gonneke Willemsen, J. Frank Wilson, B. H. Wolffenbuttel, Alan F. Wright, L.M. Yerges-Armstrong, Tatijana Zemunik, Lina Zgaga, M. Carola Zillikens, Marek Zygmunt, The LifeLines Cohort Study, Alice M. Arnold, Dorret I. Boomsma, Julie E. Buring, Laura Crisponi, Ellen W. Demerath, Vilmundur Guðnason, Tamara B. Harris, Fang Hu, David J. Hunter, Lenore J. Launer, Andres Metspalu, Grant W. Montgomery, B. A. Oostra, Paul M. Ridker, Serena Sanna, David Schlessinger, T. D. Spector, K. Stefansson, Elizabeth A. Streeten, U. Thorsteinsdottir, Manuela Uda, André G. Uitterlinden, Cornelia M. van Duijn, Henry Völzke, Alison D. Murray, Joanne M. Murabito, Jenny A. Visser, Kathryn L. Lunetta - Nature Genetics 2012 cited by 378

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 x 10(-8)). 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-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.