Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
Stolk L., Perry JRB., Chasman DI., He C., Mangino M., Sulem P., Barbalic M., Broer L., Byrne EM., Ernst F., Esko T., Franceschini N., Gudbjartsson DF., Hottenga J-J., Kraft P., McArdle PF., Porcu E., Shin S-Y., Smith AV., van Wingerden S., Zhai G., Zhuang WV., Albrecht E., Alizadeh BZ., Aspelund T., Bandinelli S., Lauc LB., Beckmann JS., Boban M., Boerwinkle E., Broekmans FJ., Burri A., Campbell H., Chanock SJ., Chen C., Cornelis MC., Corre T., Coviello AD., d'Adamo P., Davies G., de Faire U., de Geus EJC., Deary IJ., Dedoussis GVZ., Deloukas P., Ebrahim S., Eiriksdottir G., Emilsson V., Eriksson JG., Fauser BCJM., Ferreli L., Ferrucci L., Fischer K., Folsom AR., Garcia ME., Gasparini P., Gieger C., Glazer N., Grobbee DE., Hall P., Haller T., Hankinson SE., Hass M., Hayward C., Heath AC., Hofman A., Ingelsson E., Janssens ACJW., Johnson AD., Karasik D., Kardia SLR., Keyzer J., Kiel DP., Kolcic I., Kutalik Z., Lahti J., Lai S., Laisk T., Laven JSE., Lawlor DA., Liu J., Lopez LM., Louwers YV., Magnusson PKE., Marongiu M., Martin NG., Klaric IM., Masciullo C., McKnight B., Medland SE., Melzer D., Mooser V., Navarro P., Newman AB., Nyholt DR., Onland-Moret NC., Palotie A., Paré G., Parker AN., Pedersen NL., Peeters PHM., Pistis G., Plump AS., Polasek O., Pop VJM., Psaty BM., Räikkönen K., Rehnberg E., Rotter JI., Rudan I., Sala C., Salumets A., Scuteri A., Singleton A., Smith JA., Snieder H., Soranzo N., Stacey SN., Starr JM., Stathopoulou MG., Stirrups K., Stolk RP., Styrkarsdottir U., Sun YV., Tenesa A., Thorand B., Toniolo D., Tryggvadottir L., Tsui K., Ulivi S., van Dam RM., van der Schouw YT., van Gils CH., van Nierop P., Vink JM., Visscher PM., Voorhuis M., Waeber G., Wallaschofski H., Wichmann HE., Widen E., Wijnands-van Gent CJM., Willemsen G., Wilson JF., Wolffenbuttel BHR., Wright AF., Yerges-Armstrong LM., Zemunik T., Zgaga L., Zillikens MC., Zygmunt M., LifeLines Cohort Study None., Arnold AM., Boomsma DI., Buring JE., Crisponi L., Demerath EW., Gudnason V., Harris TB., Hu FB., Hunter DJ., Launer LJ., Metspalu A., Montgomery GW., Oostra BA., Ridker PM., Sanna S., Schlessinger D., Spector TD., Stefansson K., Streeten EA., Thorsteinsdottir U., Uda M., Uitterlinden AG., van Duijn CM., Völzke H., Murray A., Murabito JM., Visser JA., Lunetta KL.
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.