Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

FR Day; KS Ruth; DJ Thompson; KL Lunetta; N Pervjakova; DI Chasman; Lisette Stolk; HK Finucane; P Sulem; B Bulik-Sullivan; T Esko; AD Johnson; CE Elks; N Franceschini; CY He; E Altmaier; JA Brody; LL Franke; JE Huffman; MF Keller; PF McArdle; T Nutile; E Porcu; A Robino; LM Rose; UM Schick; JA Smith; A Teumer; M Traglia; D Vuckovic; J Yao; W Zhao; E Albrecht; Najaf Amin; T Corre; JJ (Jouke Jan) Hottenga; M Mangino; AV Smith; T Tanaka; GR Abecasis; IL Andrulis; H Anton-Culver; AC Antoniou; V Arndt; AM Arnold; C Barbieri; MW Beckmann; A Beeghly-Fadiel; J Benitez; L Bernstein; SJ Bielinski; C Blomqvist; E Boerwinkle; NV Bogdanova; SE Bojesen; MK Bolla; AL Borresen-Dale; TS Boutin; H Brauch; H Brenner; T Bruning; B Burwinkel; A (Archie) Campbell; H Campbell; SJ Chanock; JR Chapman; YDI Chen; G Chenevix-Trench; FJ Couch; AD Coviello; A Cox; K Czene; H Darabi; I de Vivo; EW Demerath; J Dennis; P Devilee; T Dork; I dos-Santos-Silva; AM Dunning; JD Eicher; PA Fasching; JD Faul; J Figueroa; D Flesch-Janys; I Gandin; ME Garcia; M Garcia-Closas; GG Giles; GG Girotto; MS Goldberg; A Gonzalez-Neira; MO Goodarzi; ML Grove; DF Gudbjartsson; P Guenel; XQ Guo; CA Haiman; P Hall; U Hamann; BE Henderson; LJ Hocking; Bert Hofman; G Homuth; Maartje Hooning; JL Hopper; FB Hu; JY Huang; K Humphreys; DJ Hunter; A Jakubowska; SE Jones; M Kabisch; D Karasik; JA Knight; I Kolcic; C Kooperberg; VM Kosma; J Kriebel; V Kristensen; D Lambrechts; C Langenberg; JM Li; X Li; S Lindstrom; YM Liu; JN Luan; J Lubinski; R Magi; A Mannermaa; J Manz; S Margolin; J Marten; NG Martin; C Masciullo; A Meindl; K Michailidou; E Mihailov; L Milani; RL Milne; M Muller-Nurasyid; M Nalls; BM Neale; H Nevanlinna; P Neven; AB Newman; BG Nordestgaard; JE Olson; S Padmanabhan; P Peterlongo; U Peters; A Petersmann; J Peto; PDP Pharoah; NN Pirastu; A Pirie; G Pistis; O Polasek; D Porteous; BM Psaty; K Pylkas; P Radice; LJ Raffel; Fernando Rivadeneira; I Rudan; A Rudolph; D Ruggiero; CF Sala; S Sanna; EJ Sawyer; D Schlessinger; MK (Marjanka) Schmidt; F Schmidt; RK Schmutzler; MJ Schoemaker; RA Scott; Caroline Seynaeve; J Simard; R Sorice; MC Southey; D Stockl; K Strauch; A Swerdlow; KD Taylor; U Thorsteinsdottir; AE Toland; I Tomlinson; T Truong; L Tryggvadottir; ST Turner; D Vozzi; Q (Qing) Wang; M Wellons; G Willemsen; JF Wilson; R Winqvist; BBHR Wolffenbuttel; AF Wright; D Yannoukakos; T Zemunik; W Zheng; M Zygmunt; S Bergmann; DI Boomsma; JE Buring; L Ferrucci; GW Montgomery; V Gudnason; TD Spector; Cornelia Duijn; BZ Alizadeh; M Ciullo; L Crisponi; DF Easton; PP Gasparini; C Gieger; TB Harris; C Hayward; SLR Kardia; P Kraft; B McKnight; A Metspalu; AC Morrison; AP Reiner; PM Ridker; JI Rotter; D Toniolo; André Uitterlinden; S Ulivi; H Volzke; NJ Wareham; DR Weir; LM Yerges-Armstrong; AL Price; K Stefansson; Jenny Visser; KK Ong; J Chang-Claude; JM Murabito; JRB Perry; A Murray

doi:10.1038/ng.3412

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

FR Day, KS Ruth, DJ Thompson, KL Lunetta, N Pervjakova, DI Chasman, Lisette Stolk, HK Finucane, P Sulem, B Bulik-Sullivan, T Esko, AD Johnson, CE Elks, N Franceschini, CY He, E Altmaier, JA Brody, LL Franke, JE Huffman, MF KellerPF McArdle, T Nutile, E Porcu, A Robino, LM Rose, UM Schick, JA Smith, A Teumer, M Traglia, D Vuckovic, J Yao, W Zhao, E Albrecht, Najaf Amin, T Corre, JJ (Jouke Jan) Hottenga, M Mangino, AV Smith, T Tanaka, GR Abecasis, IL Andrulis, H Anton-Culver, AC Antoniou, V Arndt, AM Arnold, C Barbieri, MW Beckmann, A Beeghly-Fadiel, J Benitez, L Bernstein, SJ Bielinski, C Blomqvist, E Boerwinkle, NV Bogdanova, SE Bojesen, MK Bolla, AL Borresen-Dale, TS Boutin, H Brauch, H Brenner, T Bruning, B Burwinkel, A (Archie) Campbell, H Campbell, SJ Chanock, JR Chapman, YDI Chen, G Chenevix-Trench, FJ Couch, AD Coviello, A Cox, K Czene, H Darabi, I de Vivo, EW Demerath, J Dennis, P Devilee, T Dork, I dos-Santos-Silva, AM Dunning, JD Eicher, PA Fasching, JD Faul, J Figueroa, D Flesch-Janys, I Gandin, ME Garcia, M Garcia-Closas, GG Giles, GG Girotto, MS Goldberg, A Gonzalez-Neira, MO Goodarzi, ML Grove, DF Gudbjartsson, P Guenel, XQ Guo, CA Haiman, P Hall, U Hamann, BE Henderson, LJ Hocking, Bert Hofman, G Homuth, Maartje Hooning, JL Hopper, FB Hu, JY Huang, K Humphreys, DJ Hunter, A Jakubowska, SE Jones, M Kabisch, D Karasik, JA Knight, I Kolcic, C Kooperberg, VM Kosma, J Kriebel, V Kristensen, D Lambrechts, C Langenberg, JM Li, X Li, S Lindstrom, YM Liu, JN Luan, J Lubinski, R Magi, A Mannermaa, J Manz, S Margolin, J Marten, NG Martin, C Masciullo, A Meindl, K Michailidou, E Mihailov, L Milani, RL Milne, M Muller-Nurasyid, M Nalls, BM Neale, H Nevanlinna, P Neven, AB Newman, BG Nordestgaard, JE Olson, S Padmanabhan, P Peterlongo, U Peters, A Petersmann, J Peto, PDP Pharoah, NN Pirastu, A Pirie, G Pistis, O Polasek, D Porteous, BM Psaty, K Pylkas, P Radice, LJ Raffel, Fernando Rivadeneira, I Rudan, A Rudolph, D Ruggiero, CF Sala, S Sanna, EJ Sawyer, D Schlessinger, MK (Marjanka) Schmidt, F Schmidt, RK Schmutzler, MJ Schoemaker, RA Scott, Caroline Seynaeve, J Simard, R Sorice, MC Southey, D Stockl, K Strauch, A Swerdlow, KD Taylor, U Thorsteinsdottir, AE Toland, I Tomlinson, T Truong, L Tryggvadottir, ST Turner, D Vozzi, Q (Qing) Wang, M Wellons, G Willemsen, JF Wilson, R Winqvist, BBHR Wolffenbuttel, AF Wright, D Yannoukakos, T Zemunik, W Zheng, M Zygmunt, S Bergmann, DI Boomsma, JE Buring, L Ferrucci, GW Montgomery, V Gudnason, TD Spector, Cornelia Duijn, BZ Alizadeh, M Ciullo, L Crisponi, DF Easton, PP Gasparini, C Gieger, TB Harris, C Hayward, SLR Kardia, P Kraft, B McKnight, A Metspalu, AC Morrison, AP Reiner, PM Ridker, JI Rotter, D Toniolo, André Uitterlinden, S Ulivi, H Volzke, NJ Wareham, DR Weir, LM Yerges-Armstrong, AL Price, K Stefansson, Jenny Visser, KK Ong, J Chang-Claude, JM Murabito, JRB Perry, A Murray

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

312 Citations (Scopus)

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Original language	Undefined/Unknown
Pages (from-to)	1294-+
Journal	Nature Genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3412
Publication status	Published - 2015

Research programs

EMC MM-01-39-04
EMC MM-01-39-09-A
EMC MM-03-86-01
EMC NIHES-01-64-02

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.3412

http://hdl.handle.net/1765/94615

Cite this

Day, FR., Ruth, KS., Thompson, DJ., Lunetta, KL., Pervjakova, N., Chasman, DI., Stolk, L., Finucane, HK., Sulem, P., Bulik-Sullivan, B., Esko, T., Johnson, AD., Elks, CE., Franceschini, N., He, CY., Altmaier, E., Brody, JA., Franke, LL., Huffman, JE., ... Murray, A. (2015). Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), 1294-+. https://doi.org/10.1038/ng.3412

@article{ff56741397a84d85b0b7be1b821bf7a4,

title = "Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair",

abstract = "Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.",

author = "FR Day and KS Ruth and DJ Thompson and KL Lunetta and N Pervjakova and DI Chasman and Lisette Stolk and HK Finucane and P Sulem and B Bulik-Sullivan and T Esko and AD Johnson and CE Elks and N Franceschini and CY He and E Altmaier and JA Brody and LL Franke and JE Huffman and MF Keller and PF McArdle and T Nutile and E Porcu and A Robino and LM Rose and UM Schick and JA Smith and A Teumer and M Traglia and D Vuckovic and J Yao and W Zhao and E Albrecht and Najaf Amin and T Corre and Hottenga, {JJ (Jouke Jan)} and M Mangino and AV Smith and T Tanaka and GR Abecasis and IL Andrulis and H Anton-Culver and AC Antoniou and V Arndt and AM Arnold and C Barbieri and MW Beckmann and A Beeghly-Fadiel and J Benitez and L Bernstein and SJ Bielinski and C Blomqvist and E Boerwinkle and NV Bogdanova and SE Bojesen and MK Bolla and AL Borresen-Dale and TS Boutin and H Brauch and H Brenner and T Bruning and B Burwinkel and Campbell, {A (Archie)} and H Campbell and SJ Chanock and JR Chapman and YDI Chen and G Chenevix-Trench and FJ Couch and AD Coviello and A Cox and K Czene and H Darabi and {de Vivo}, I and EW Demerath and J Dennis and P Devilee and T Dork and I dos-Santos-Silva and AM Dunning and JD Eicher and PA Fasching and JD Faul and J Figueroa and D Flesch-Janys and I Gandin and ME Garcia and M Garcia-Closas and GG Giles and GG Girotto and MS Goldberg and A Gonzalez-Neira and MO Goodarzi and ML Grove and DF Gudbjartsson and P Guenel and XQ Guo and CA Haiman and P Hall and U Hamann and BE Henderson and LJ Hocking and Bert Hofman and G Homuth and Maartje Hooning and JL Hopper and FB Hu and JY Huang and K Humphreys and DJ Hunter and A Jakubowska and SE Jones and M Kabisch and D Karasik and JA Knight and I Kolcic and C Kooperberg and VM Kosma and J Kriebel and V Kristensen and D Lambrechts and C Langenberg and JM Li and X Li and S Lindstrom and YM Liu and JN Luan and J Lubinski and R Magi and A Mannermaa and J Manz and S Margolin and J Marten and NG Martin and C Masciullo and A Meindl and K Michailidou and E Mihailov and L Milani and RL Milne and M Muller-Nurasyid and M Nalls and BM Neale and H Nevanlinna and P Neven and AB Newman and BG Nordestgaard and JE Olson and S Padmanabhan and P Peterlongo and U Peters and A Petersmann and J Peto and PDP Pharoah and NN Pirastu and A Pirie and G Pistis and O Polasek and D Porteous and BM Psaty and K Pylkas and P Radice and LJ Raffel and Fernando Rivadeneira and I Rudan and A Rudolph and D Ruggiero and CF Sala and S Sanna and EJ Sawyer and D Schlessinger and Schmidt, {MK (Marjanka)} and F Schmidt and RK Schmutzler and MJ Schoemaker and RA Scott and Caroline Seynaeve and J Simard and R Sorice and MC Southey and D Stockl and K Strauch and A Swerdlow and KD Taylor and U Thorsteinsdottir and AE Toland and I Tomlinson and T Truong and L Tryggvadottir and ST Turner and D Vozzi and Wang, {Q (Qing)} and M Wellons and G Willemsen and JF Wilson and R Winqvist and BBHR Wolffenbuttel and AF Wright and D Yannoukakos and T Zemunik and W Zheng and M Zygmunt and S Bergmann and DI Boomsma and JE Buring and L Ferrucci and GW Montgomery and V Gudnason and TD Spector and Cornelia Duijn and BZ Alizadeh and M Ciullo and L Crisponi and DF Easton and PP Gasparini and C Gieger and TB Harris and C Hayward and SLR Kardia and P Kraft and B McKnight and A Metspalu and AC Morrison and AP Reiner and PM Ridker and JI Rotter and D Toniolo and Andr{\'e} Uitterlinden and S Ulivi and H Volzke and NJ Wareham and DR Weir and LM Yerges-Armstrong and AL Price and K Stefansson and Jenny Visser and KK Ong and J Chang-Claude and JM Murabito and JRB Perry and A Murray",

year = "2015",

doi = "10.1038/ng.3412",

language = "Undefined/Unknown",

volume = "47",

pages = "1294--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

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Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, CY, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, JJ, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Boutin, TS, Brauch, H, Brenner, H, Bruning, T, Burwinkel, B, Campbell, A, Campbell, H, Chanock, SJ, Chapman, JR, Chen, YDI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, de Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dork, T, dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, Garcia-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonzalez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guenel, P, Guo, XQ, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, B, Homuth, G, Hooning, M, Hopper, JL, Hu, FB, Huang, JY, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, VM, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, JM, Li, X, Lindstrom, S, Liu, YM, Luan, JN, Lubinski, J, Magi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Muller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkas, K, Radice, P, Raffel, LJ, Rivadeneira, F, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK, Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, C, Simard, J, Sorice, R, Southey, MC, Stockl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q, Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, Duijn, C, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, A, Ulivi, S, Volzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, J, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB & Murray, A 2015, 'Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair', Nature Genetics, vol. 47, no. 11, pp. 1294-+. https://doi.org/10.1038/ng.3412

TY - JOUR

T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

AU - Day, FR

AU - Ruth, KS

AU - Thompson, DJ

AU - Lunetta, KL

AU - Pervjakova, N

AU - Chasman, DI

AU - Stolk, Lisette

AU - Finucane, HK

AU - Sulem, P

AU - Bulik-Sullivan, B

AU - Esko, T

AU - Johnson, AD

AU - Elks, CE

AU - Franceschini, N

AU - He, CY

AU - Altmaier, E

AU - Brody, JA

AU - Franke, LL

AU - Huffman, JE

AU - Keller, MF

AU - McArdle, PF

AU - Nutile, T

AU - Porcu, E

AU - Robino, A

AU - Rose, LM

AU - Schick, UM

AU - Smith, JA

AU - Teumer, A

AU - Traglia, M

AU - Vuckovic, D

AU - Yao, J

AU - Zhao, W

AU - Albrecht, E

AU - Amin, Najaf

AU - Corre, T

AU - Hottenga, JJ (Jouke Jan)

AU - Mangino, M

AU - Smith, AV

AU - Tanaka, T

AU - Abecasis, GR

AU - Andrulis, IL

AU - Anton-Culver, H

AU - Antoniou, AC

AU - Arndt, V

AU - Arnold, AM

AU - Barbieri, C

AU - Beckmann, MW

AU - Beeghly-Fadiel, A

AU - Benitez, J

AU - Bernstein, L

AU - Bielinski, SJ

AU - Blomqvist, C

AU - Boerwinkle, E

AU - Bogdanova, NV

AU - Bojesen, SE

AU - Bolla, MK

AU - Borresen-Dale, AL

AU - Boutin, TS

AU - Brauch, H

AU - Brenner, H

AU - Bruning, T

AU - Burwinkel, B

AU - Campbell, A (Archie)

AU - Campbell, H

AU - Chanock, SJ

AU - Chapman, JR

AU - Chen, YDI

AU - Chenevix-Trench, G

AU - Couch, FJ

AU - Coviello, AD

AU - Cox, A

AU - Czene, K

AU - Darabi, H

AU - de Vivo, I

AU - Demerath, EW

AU - Dennis, J

AU - Devilee, P

AU - Dork, T

AU - dos-Santos-Silva, I

AU - Dunning, AM

AU - Eicher, JD

AU - Fasching, PA

AU - Faul, JD

AU - Figueroa, J

AU - Flesch-Janys, D

AU - Gandin, I

AU - Garcia, ME

AU - Garcia-Closas, M

AU - Giles, GG

AU - Girotto, GG

AU - Goldberg, MS

AU - Gonzalez-Neira, A

AU - Goodarzi, MO

AU - Grove, ML

AU - Gudbjartsson, DF

AU - Guenel, P

AU - Guo, XQ

AU - Haiman, CA

AU - Hall, P

AU - Hamann, U

AU - Henderson, BE

AU - Hocking, LJ

AU - Hofman, Bert

AU - Homuth, G

AU - Hooning, Maartje

AU - Hopper, JL

AU - Hu, FB

AU - Huang, JY

AU - Humphreys, K

AU - Hunter, DJ

AU - Jakubowska, A

AU - Jones, SE

AU - Kabisch, M

AU - Karasik, D

AU - Knight, JA

AU - Kolcic, I

AU - Kooperberg, C

AU - Kosma, VM

AU - Kriebel, J

AU - Kristensen, V

AU - Lambrechts, D

AU - Langenberg, C

AU - Li, JM

AU - Li, X

AU - Lindstrom, S

AU - Liu, YM

AU - Luan, JN

AU - Lubinski, J

AU - Magi, R

AU - Mannermaa, A

AU - Manz, J

AU - Margolin, S

AU - Marten, J

AU - Martin, NG

AU - Masciullo, C

AU - Meindl, A

AU - Michailidou, K

AU - Mihailov, E

AU - Milani, L

AU - Milne, RL

AU - Muller-Nurasyid, M

AU - Nalls, M

AU - Neale, BM

AU - Nevanlinna, H

AU - Neven, P

AU - Newman, AB

AU - Nordestgaard, BG

AU - Olson, JE

AU - Padmanabhan, S

AU - Peterlongo, P

AU - Peters, U

AU - Petersmann, A

AU - Peto, J

AU - Pharoah, PDP

AU - Pirastu, NN

AU - Pirie, A

AU - Pistis, G

AU - Polasek, O

AU - Porteous, D

AU - Psaty, BM

AU - Pylkas, K

AU - Radice, P

AU - Raffel, LJ

AU - Rivadeneira, Fernando

AU - Rudan, I

AU - Rudolph, A

AU - Ruggiero, D

AU - Sala, CF

AU - Sanna, S

AU - Sawyer, EJ

AU - Schlessinger, D

AU - Schmidt, MK (Marjanka)

AU - Schmidt, F

AU - Schmutzler, RK

AU - Schoemaker, MJ

AU - Scott, RA

AU - Seynaeve, Caroline

AU - Simard, J

AU - Sorice, R

AU - Southey, MC

AU - Stockl, D

AU - Strauch, K

AU - Swerdlow, A

AU - Taylor, KD

AU - Thorsteinsdottir, U

AU - Toland, AE

AU - Tomlinson, I

AU - Truong, T

AU - Tryggvadottir, L

AU - Turner, ST

AU - Vozzi, D

AU - Wang, Q (Qing)

AU - Wellons, M

AU - Willemsen, G

AU - Wilson, JF

AU - Winqvist, R

AU - Wolffenbuttel, BBHR

AU - Wright, AF

AU - Yannoukakos, D

AU - Zemunik, T

AU - Zheng, W

AU - Zygmunt, M

AU - Bergmann, S

AU - Boomsma, DI

AU - Buring, JE

AU - Ferrucci, L

AU - Montgomery, GW

AU - Gudnason, V

AU - Spector, TD

AU - Duijn, Cornelia

AU - Alizadeh, BZ

AU - Ciullo, M

AU - Crisponi, L

AU - Easton, DF

AU - Gasparini, PP

AU - Gieger, C

AU - Harris, TB

AU - Hayward, C

AU - Kardia, SLR

AU - Kraft, P

AU - McKnight, B

AU - Metspalu, A

AU - Morrison, AC

AU - Reiner, AP

AU - Ridker, PM

AU - Rotter, JI

AU - Toniolo, D

AU - Uitterlinden, André

AU - Ulivi, S

AU - Volzke, H

AU - Wareham, NJ

AU - Weir, DR

AU - Yerges-Armstrong, LM

AU - Price, AL

AU - Stefansson, K

AU - Visser, Jenny

AU - Ong, KK

AU - Chang-Claude, J

AU - Murabito, JM

AU - Perry, JRB

AU - Murray, A

PY - 2015

Y1 - 2015

N2 - Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

AB - Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

U2 - 10.1038/ng.3412

DO - 10.1038/ng.3412

M3 - Article

C2 - 26414677

SN - 1061-4036

VL - 47

SP - 1294-+

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -