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

Lisette Stolk; JRB Perry; DI Chasman; CY He; M Mangino; P Sulem; M Barbalic; Linda Broer; EM Byrne; F Ernst; T Esko; N Franceschini; DF Gudbjartsson; JJ (Jouke Jan) Hottenga; P Kraft; PF McArdle; E Porcu; SY Shin; AV Smith; S van Wingerden; G Zhai; WV Zhuang; E Albrecht; BZ Alizadeh; T Aspelund; S Bandinelli; LB Lauc; JS Beckmann; M Boban; E Boerwinkle; FJ Broekmans; A Burri; H Campbell; SJ Chanock; C (Christopher Li Hsian) Chen; MC Cornelis; T Corre; AD Coviello; P d'Adamo; G Davies; U de Faire; EJC de Geus; IJ Deary; GVZ Dedoussis; P Deloukas; S Ebrahim; G Eiriksdottir; V Emilsson; JG Eriksson; BCJM (Bart) Fauser; L Ferreli; L Ferrucci; K (Kirsten) Fischer; AR Folsom; ME Garcia; P Gasparini; C Gieger; N Glazer; DE (Diederick) Grobbee; P Hall; T Haller; SE Hankinson; M Hass; C Hayward; AC Heath; Bert Hofman; E Ingelsson; Cecile Janssens; AD Johnson; D Karasik; SLR Kardia; J Keyzer; DP Kiel; I Kolcic; Z Kutalik; J Lahti; S Lai; T Laisk; Joop Laven; DA Lawlor; JJ Liu; LM Lopez; Yvonne Louwers; PKE Magnusson; M Marongiu; NG Martin; IM Klaric; C Masciullo; B McKnight; SE Medland; D Melzer; V Mooser; P Navarro; AB Newman; DR Nyholt; NC Onland-Moret; A Palotie; G Pare; AN Parker; NL Pedersen; PHM Peeters; G Pistis; AS Plump; O Polasek; VJM Pop; BM Psaty; K Raikkonen; E Rehnberg; JI Rotter; I Rudan; C Sala; A Salumets; A Scuteri; A Singleton; JA Smith; H Snieder; N Soranzo; SN Stacey; JM Starr; MG Stathopoulou; K Stirrups; RP (Ronald) Stolk; U Styrkarsdottir; YV Sun; A Tenesa; B Thorand; D Toniolo; L Tryggvadottir; K Tsui; S Ulivi; RM van Dam; YT van der Schouw; CH van Gils; P van Nierop; JM Vink; PM Visscher; M Voorhuis; G Waeber; H Wallaschofski; HE Wichmann; E Widen; CJM van Gent; G Willemsen; JF Wilson; BHR Wolffenbuttel; AF Wright; LM Yerges-Armstrong; T Zemunik; L Zgaga; M.C. Zillikens; M Zygmunt; AM Arnold; DI Boomsma; JE Buring; L Crisponi; EW Demerath; V Gudnason; TB Harris; FB Hu; DJ Hunter; LJ (Lenore) Launer; A Metspalu; GW Montgomery; Ben Oostra; PM Ridker; S Sanna; D Schlessinger; TD Spector; K Stefansson; EA Streeten; U Thorsteinsdottir; M Uda; André Uitterlinden; Cornelia Duijn; H Volzke; A Murray; JM Murabito; Jenny Visser; KL Lunetta

doi:10.1038/ng.1051

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

Lisette Stolk, JRB Perry, DI Chasman, CY He, M Mangino, P Sulem, M Barbalic, Linda Broer, EM Byrne, F Ernst, T Esko, N Franceschini, DF Gudbjartsson, JJ (Jouke Jan) Hottenga, P Kraft, PF McArdle, E Porcu, SY Shin, AV Smith, S van WingerdenG Zhai, WV Zhuang, E Albrecht, BZ Alizadeh, T Aspelund, S Bandinelli, LB Lauc, JS Beckmann, M Boban, E Boerwinkle, FJ Broekmans, A Burri, H Campbell, SJ Chanock, C (Christopher Li Hsian) Chen, MC Cornelis, T Corre, AD Coviello, P d'Adamo, G Davies, U de Faire, EJC de Geus, IJ Deary, GVZ Dedoussis, P Deloukas, S Ebrahim, G Eiriksdottir, V Emilsson, JG Eriksson, BCJM (Bart) Fauser, L Ferreli, L Ferrucci, K (Kirsten) Fischer, AR Folsom, ME Garcia, P Gasparini, C Gieger, N Glazer, DE (Diederick) Grobbee, P Hall, T Haller, SE Hankinson, M Hass, C Hayward, AC Heath, Bert Hofman, E Ingelsson, Cecile Janssens, AD Johnson, D Karasik, SLR Kardia, J Keyzer, DP Kiel, I Kolcic, Z Kutalik, J Lahti, S Lai, T Laisk, Joop Laven, DA Lawlor, JJ Liu, LM Lopez, Yvonne Louwers, PKE Magnusson, M Marongiu, NG Martin, IM Klaric, C Masciullo, B McKnight, SE Medland, D Melzer, V Mooser, P Navarro, AB Newman, DR Nyholt, NC Onland-Moret, A Palotie, G Pare, AN Parker, NL Pedersen, PHM Peeters, G Pistis, AS Plump, O Polasek, VJM Pop, BM Psaty, K Raikkonen, E Rehnberg, JI Rotter, I Rudan, C Sala, A Salumets, A Scuteri, A Singleton, JA Smith, H Snieder, N Soranzo, SN Stacey, JM Starr, MG Stathopoulou, K Stirrups, RP (Ronald) Stolk, U Styrkarsdottir, YV Sun, A Tenesa, B Thorand, D Toniolo, L Tryggvadottir, K Tsui, S Ulivi, RM van Dam, YT van der Schouw, CH van Gils, P van Nierop, JM Vink, PM Visscher, M Voorhuis, G Waeber, H Wallaschofski, HE Wichmann, E Widen, CJM van Gent, G Willemsen, JF Wilson, BHR Wolffenbuttel, AF Wright, LM Yerges-Armstrong, T Zemunik, L Zgaga, M.C. Zillikens, M Zygmunt, AM Arnold, DI Boomsma, JE Buring, L Crisponi, EW Demerath, V Gudnason, TB Harris, FB Hu, DJ Hunter, LJ (Lenore) Launer, A Metspalu, GW Montgomery, Ben Oostra, PM Ridker, S Sanna, D Schlessinger, TD Spector, K Stefansson, EA Streeten, U Thorsteinsdottir, M Uda, André Uitterlinden, Cornelia Duijn, H Volzke, A Murray, JM Murabito, Jenny Visser, KL Lunetta

Research output: Contribution to journal › Article › Academic › peer-review

292 Citations (Scopus)

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 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-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Original language	Undefined/Unknown
Pages (from-to)	260-U55
Journal	Nature Genetics
Volume	44
Issue number	3
DOIs	https://doi.org/10.1038/ng.1051
Publication status	Published - 2012

Research programs

EMC MGC-02-96-01
EMC MM-01-39-04
EMC MM-01-39-09-A
EMC MM-01-52-07
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-01-64-03

Access to Document

10.1038/ng.1051

http://hdl.handle.net/1765/60316

Cite this

Stolk, L., Perry, JRB., Chasman, DI., He, CY., Mangino, M., Sulem, P., Barbalic, M., Broer, L., Byrne, EM., Ernst, F., Esko, T., Franceschini, N., Gudbjartsson, DF., Hottenga, JJ., Kraft, P., McArdle, PF., Porcu, E., Shin, SY., Smith, AV., ... Lunetta, KL. (2012). Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nature Genetics, 44(3), 260-U55. https://doi.org/10.1038/ng.1051

@article{2785810ffb7946b18c78d18493a7cbc3,

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

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 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-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.",

author = "Lisette Stolk and JRB Perry and DI Chasman and CY He and M Mangino and P Sulem and M Barbalic and Linda Broer and EM Byrne and F Ernst and T Esko and N Franceschini and DF Gudbjartsson and Hottenga, {JJ (Jouke Jan)} and P Kraft and PF McArdle and E Porcu and SY Shin and AV Smith and {van Wingerden}, S and G Zhai and WV Zhuang and E Albrecht and BZ Alizadeh and T Aspelund and S Bandinelli and LB Lauc and JS Beckmann and M Boban and E Boerwinkle and FJ Broekmans and A Burri and H Campbell and SJ Chanock and Chen, {C (Christopher Li Hsian)} and MC Cornelis and T Corre and AD Coviello and P d'Adamo and G Davies and {de Faire}, U and {de Geus}, EJC and IJ Deary and GVZ Dedoussis and P Deloukas and S Ebrahim and G Eiriksdottir and V Emilsson and JG Eriksson and Fauser, {BCJM (Bart)} and L Ferreli and L Ferrucci and Fischer, {K (Kirsten)} and AR Folsom and ME Garcia and P Gasparini and C Gieger and N Glazer and Grobbee, {DE (Diederick)} and P Hall and T Haller and SE Hankinson and M Hass and C Hayward and AC Heath and Bert Hofman and E Ingelsson and Cecile Janssens and AD Johnson and D Karasik and SLR Kardia and J Keyzer and DP Kiel and I Kolcic and Z Kutalik and J Lahti and S Lai and T Laisk and Joop Laven and DA Lawlor and JJ Liu and LM Lopez and Yvonne Louwers and PKE Magnusson and M Marongiu and NG Martin and IM Klaric and C Masciullo and B McKnight and SE Medland and D Melzer and V Mooser and P Navarro and AB Newman and DR Nyholt and NC Onland-Moret and A Palotie and G Pare and AN Parker and NL Pedersen and PHM Peeters and G Pistis and AS Plump and O Polasek and VJM Pop and BM Psaty and K Raikkonen and E Rehnberg and JI Rotter and I Rudan and C Sala and A Salumets and A Scuteri and A Singleton and JA Smith and H Snieder and N Soranzo and SN Stacey and JM Starr and MG Stathopoulou and K Stirrups and Stolk, {RP (Ronald)} and U Styrkarsdottir and YV Sun and A Tenesa and B Thorand and D Toniolo and L Tryggvadottir and K Tsui and S Ulivi and {van Dam}, RM and {van der Schouw}, YT and {van Gils}, CH and {van Nierop}, P and JM Vink and PM Visscher and M Voorhuis and G Waeber and H Wallaschofski and HE Wichmann and E Widen and {van Gent}, CJM and G Willemsen and JF Wilson and BHR Wolffenbuttel and AF Wright and LM Yerges-Armstrong and T Zemunik and L Zgaga and M.C. Zillikens and M Zygmunt and AM Arnold and DI Boomsma and JE Buring and L Crisponi and EW Demerath and V Gudnason and TB Harris and FB Hu and DJ Hunter and Launer, {LJ (Lenore)} and A Metspalu and GW Montgomery and Ben Oostra and PM Ridker and S Sanna and D Schlessinger and TD Spector and K Stefansson and EA Streeten and U Thorsteinsdottir and M Uda and Andr{\'e} Uitterlinden and Cornelia Duijn and H Volzke and A Murray and JM Murabito and Jenny Visser and KL Lunetta",

year = "2012",

doi = "10.1038/ng.1051",

language = "Undefined/Unknown",

volume = "44",

pages = "260--U55",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Stolk, L, Perry, JRB, Chasman, DI, He, CY, Mangino, M, Sulem, P, Barbalic, M, Broer, L, Byrne, EM, Ernst, F, Esko, T, Franceschini, N, Gudbjartsson, DF, Hottenga, JJ, Kraft, P, McArdle, PF, Porcu, E, Shin, SY, 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, B, Ingelsson, E, Janssens, C, Johnson, AD, Karasik, D, Kardia, SLR, Keyzer, J, Kiel, DP, Kolcic, I, Kutalik, Z, Lahti, J, Lai, S, Laisk, T, Laven, J, Lawlor, DA, Liu, JJ, Lopez, LM, Louwers, Y, 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, Pare, G, Parker, AN, Pedersen, NL, Peeters, PHM, Pistis, G, Plump, AS, Polasek, O, Pop, VJM, Psaty, BM, Raikkonen, 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, van Gent, CJM, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wright, AF, Yerges-Armstrong, LM, Zemunik, T, Zgaga, L, Zillikens, MC, Zygmunt, M, 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, B, Ridker, PM, Sanna, S, Schlessinger, D, Spector, TD, Stefansson, K, Streeten, EA, Thorsteinsdottir, U, Uda, M, Uitterlinden, A, Duijn, C, Volzke, H, Murray, A, Murabito, JM, Visser, J & Lunetta, KL 2012, 'Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways', Nature Genetics, vol. 44, no. 3, pp. 260-U55. https://doi.org/10.1038/ng.1051

TY - JOUR

T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

AU - Stolk, Lisette

AU - Perry, JRB

AU - Chasman, DI

AU - He, CY

AU - Mangino, M

AU - Sulem, P

AU - Barbalic, M

AU - Broer, Linda

AU - Byrne, EM

AU - Ernst, F

AU - Esko, T

AU - Franceschini, N

AU - Gudbjartsson, DF

AU - Hottenga, JJ (Jouke Jan)

AU - Kraft, P

AU - McArdle, PF

AU - Porcu, E

AU - Shin, SY

AU - Smith, AV

AU - van Wingerden, S

AU - Zhai, G

AU - Zhuang, WV

AU - Albrecht, E

AU - Alizadeh, BZ

AU - Aspelund, T

AU - Bandinelli, S

AU - Lauc, LB

AU - Beckmann, JS

AU - Boban, M

AU - Boerwinkle, E

AU - Broekmans, FJ

AU - Burri, A

AU - Campbell, H

AU - Chanock, SJ

AU - Chen, C (Christopher Li Hsian)

AU - Cornelis, MC

AU - Corre, T

AU - Coviello, AD

AU - d'Adamo, P

AU - Davies, G

AU - de Faire, U

AU - de Geus, EJC

AU - Deary, IJ

AU - Dedoussis, GVZ

AU - Deloukas, P

AU - Ebrahim, S

AU - Eiriksdottir, G

AU - Emilsson, V

AU - Eriksson, JG

AU - Fauser, BCJM (Bart)

AU - Ferreli, L

AU - Ferrucci, L

AU - Fischer, K (Kirsten)

AU - Folsom, AR

AU - Garcia, ME

AU - Gasparini, P

AU - Gieger, C

AU - Glazer, N

AU - Grobbee, DE (Diederick)

AU - Hall, P

AU - Haller, T

AU - Hankinson, SE

AU - Hass, M

AU - Hayward, C

AU - Heath, AC

AU - Hofman, Bert

AU - Ingelsson, E

AU - Janssens, Cecile

AU - Johnson, AD

AU - Karasik, D

AU - Kardia, SLR

AU - Keyzer, J

AU - Kiel, DP

AU - Kolcic, I

AU - Kutalik, Z

AU - Lahti, J

AU - Lai, S

AU - Laisk, T

AU - Laven, Joop

AU - Lawlor, DA

AU - Liu, JJ

AU - Lopez, LM

AU - Louwers, Yvonne

AU - Magnusson, PKE

AU - Marongiu, M

AU - Martin, NG

AU - Klaric, IM

AU - Masciullo, C

AU - McKnight, B

AU - Medland, SE

AU - Melzer, D

AU - Mooser, V

AU - Navarro, P

AU - Newman, AB

AU - Nyholt, DR

AU - Onland-Moret, NC

AU - Palotie, A

AU - Pare, G

AU - Parker, AN

AU - Pedersen, NL

AU - Peeters, PHM

AU - Pistis, G

AU - Plump, AS

AU - Polasek, O

AU - Pop, VJM

AU - Psaty, BM

AU - Raikkonen, K

AU - Rehnberg, E

AU - Rotter, JI

AU - Rudan, I

AU - Sala, C

AU - Salumets, A

AU - Scuteri, A

AU - Singleton, A

AU - Smith, JA

AU - Snieder, H

AU - Soranzo, N

AU - Stacey, SN

AU - Starr, JM

AU - Stathopoulou, MG

AU - Stirrups, K

AU - Stolk, RP (Ronald)

AU - Styrkarsdottir, U

AU - Sun, YV

AU - Tenesa, A

AU - Thorand, B

AU - Toniolo, D

AU - Tryggvadottir, L

AU - Tsui, K

AU - Ulivi, S

AU - van Dam, RM

AU - van der Schouw, YT

AU - van Gils, CH

AU - van Nierop, P

AU - Vink, JM

AU - Visscher, PM

AU - Voorhuis, M

AU - Waeber, G

AU - Wallaschofski, H

AU - Wichmann, HE

AU - Widen, E

AU - van Gent, CJM

AU - Willemsen, G

AU - Wilson, JF

AU - Wolffenbuttel, BHR

AU - Wright, AF

AU - Yerges-Armstrong, LM

AU - Zemunik, T

AU - Zgaga, L

AU - Zillikens, M.C.

AU - Zygmunt, M

AU - Arnold, AM

AU - Boomsma, DI

AU - Buring, JE

AU - Crisponi, L

AU - Demerath, EW

AU - Gudnason, V

AU - Harris, TB

AU - Hu, FB

AU - Hunter, DJ

AU - Launer, LJ (Lenore)

AU - Metspalu, A

AU - Montgomery, GW

AU - Oostra, Ben

AU - Ridker, PM

AU - Sanna, S

AU - Schlessinger, D

AU - Spector, TD

AU - Stefansson, K

AU - Streeten, EA

AU - Thorsteinsdottir, U

AU - Uda, M

AU - Uitterlinden, André

AU - Duijn, Cornelia

AU - Volzke, H

AU - Murray, A

AU - Murabito, JM

AU - Visser, Jenny

AU - Lunetta, KL

PY - 2012

Y1 - 2012

N2 - 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-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

AB - 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-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

U2 - 10.1038/ng.1051

DO - 10.1038/ng.1051

M3 - Article

C2 - 22267201

SN - 1061-4036

VL - 44

SP - 260-U55

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -