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

L. Stolk, M.C. Zillikens, A.G. Uitterlinden, J.A. Visser, A. Hofman, C.M. Van Duijn, J.R.B. Perry, D. Melzer, A. Murray, D.I. Chasman, G. Paré, J.E. Buring, L. Crisponi, P.M. Ridker, C. He, M. Mangino, G. Zhai, A. Burri, N. Soranzo, T.D. SpectorP. Sulem, D.F. Gudbjartsson, S.N. Stacey, U. Styrkarsdottir, K. Stefansson, U. Thorsteinsdottir, M. Barbalic, E. Boerwinkle, L. Broer, S. Van Wingerden, A.C.J.W. Janssens, E.M. Byrne, N.G. Martin, S.E. Medland, D.R. Nyholt, G.W. Montgomery, F. Ernst, T. Esko, K. Fischer, T. Haller, M. Hass, A. Salumets, A. Metspalu, H. Völzke, N. Franceschini, J.-J. Hottenga, E.J.C. De Geus, J.M. Vink, G. Willemsen, D.I. Boomsma, P. Kraft, C. Chen, S.E. Hankinson, F.B. Hu, D.J. Hunter, P.F. McArdle, L.M. Yerges-Armstrong, E.A. Streeten, E. Porcu, L. Ferreli, S. Lai, M. Marongiu, S. Sanna, M. Uda, S.-Y. Shin, P. Deloukas, A. Palotie, K. Stirrups, A.V. Smith, T. Aspelund, G. Eiriksdottir, V. Emilsson, V. Gudnason, L. Tryggvadottir, W.V. Zhuang, K.L. Lunetta, E. Albrecht, C. Gieger, B.Z. Alizadeh, H. Snieder, R.P. Stolk, S. Bandinelli, L.B. Lauc, J.S. Beckmann, Z. Kutalik, M. Boban, I. Kolcic, O. Polasek, I. Rudan, T. Zemunik, F.J. Broekmans, B.C.J.M. Fauser, M. Voorhuis, H. Campbell, J.F. Wilson, L. Zgaga, S.J. Chanock, M.C. Cornelis, R.M. Van Dam, T. Corre, C. Masciullo, G. Pistis, C. Sala, D. Toniolo, A.D. Coviello, N. Glazer, J.M. Murabito, A.D. Johnson, D. Karasik, D.P. Kiel, P. D'Adamo, P. Gasparini, S. Ulivi, G. Davies, I.J. Deary, L.M. Lopez, U. De Faire, J.M. Starr, P.M. Visscher, G.V.Z. Dedoussis, M.G. Stathopoulou, S. Ebrahim, J.G. Eriksson, E.W. Demerath, L. Ferrucci, A.R. Folsom, M.E. Garcia, T.B. Harris, L.J. Launer, D.E. Grobbee, N.C. Onland-Moret, P.H.M. Peeters, Y.T. Van Der Schouw, C.H. Van Gils, P. Hall, E. Ingelsson, P.K.E. Magnusson, N.L. Pedersen, E. Rehnberg, C. Hayward, P. Navarro, A. Tenesa, A.F. Wright, A.C. Heath, S.L.R. Kardia, J.A. Smith, J. Keyzer, J. Lahti, K. R Currency Signikkönen, T. Laisk, J.S.E. Laven, Y.V. Louwers, D.A. Lawlor, J. Liu, I.M. Klaric, B. McKnight, A.M. Arnold, V. Mooser, A.B. Newman, E. Widen, A.N. Parker, K. Tsui, A.S. Plump, V.J.M. Pop, B.M. Psaty, J.I. Rotter, A. Scuteri, A. Singleton, B.H.R. Wolffenbuttel, Y.V. Sun, B. Thorand, P. Van Nierop, G. Waeber, H. Wallaschofski, H.E. Wichmann, C.J.M. Wijnands-Van Gent, M. Zygmunt, B.A. Oostra, D. Schlessinger

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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(-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-κB 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
Early online date24 Jan 2012
DOIs
Publication statusPublished - 1 Mar 2012

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