Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R. B. Perry; Felix Day; Cathy E. Elks; Patrick Sulem; Deborah J. Thompson; Teresa Ferreira; Chunyan He; Daniel I. Chasman; Toenu Esko; Gudmar Thorleifsson; Eva Albrecht; Wei Q. Ang; Tanguy Corre; Diana L. Cousminer; Bjarke Feenstra; Nora Franceschini; Andrea Ganna; Andrew D. Johnson; Sanela Kjellqvist; Kathryn L. Lunetta; George McMahon; Ilja M. Nolte; Lavinia Paternoster; Eleonora Porcu; Albert V. Smith; Lisette Stolk; Alexander Teumer; Natalia Tsernikova; Emmi Tikkanen; Sheila Ulivi; Erin K. Wagner; Najaf Amin; Laura J. Bierut; Enda M. Byrne; Jouke-Jan Hottenga; Daniel L. Koller; Massimo Mangino; Tune Hannes Pers; Laura M. Yerges-Armstrong; Jing Hua Zhao; Irene L. Andrulis; Hoda Anton-Culver; Femke Atsma; Stefania Bandinelli; Matthias W. Beckmann; Javier Benitez; Carl Blomqvist; Stig E. Bojesen; Manjeet K. Bolla; Bernardo Bonanni; Hiltrud Brauch; Hermann Brenner; Julie E. Buring; Jenny Chang-Claude; Stephen Chanock; Jinhui Chen; Georgia Chenevix-Trench; J. Margriet Collee; Fergus J. Couch; David Couper; Andrea D. Coviello; Angela Cox; Kamila Czene; Adamo Pio D'adamo; George Davey Smith; Immaculata De Vivo; Ellen W. Demerath; Joe Dennis; Peter Devilee; Aida K. Dieffenbach; Alison M. Dunning; Gudny Eiriksdottir; Johan G. Eriksson; Peter A. Fasching; Luigi Ferrucci; Dieter Flesch-Janys; Henrik Flyger; Tatiana Foroud; Lude Franke; Melissa E. Garcia; Montserrat Garcia-Closas; Frank Geller; Eco E. J. de Geus; Graham G. Giles; Daniel F. Gudbjartsson; Vilmundur Gudnason; Pascal Guenel; Suiqun Guo; Per Hall; Ute Hamann; Robin Haring; Catharina A. Hartman; AndrewC Heath; Albert Hofman; Maartje J. Hooning; John L. Hopper; Frank B. Hu; David J. Hunter; David Karasik; Douglas P. Kiel; Julia A. Knight; Veli-Matti Kosma; Zoltan Kutalik; Sandra Lai; Diether Lambrechts; Annika Lindblom; Reedik Maegi; Patrik K. Magnusson; Arto Mannermaa; Nicholas G. Martin; Gisli Masson; Patrick F. McArdle; Wendy L. McArdle; Mads Melbye; Kyriaki Michailidou; Evelin Mihailov; Lili Milani; Roger L. Milne; Heli Nevanlinna; Patrick Neven; Ellen A. Nohr; Albertine J. Oldehinkel; Ben A. Oostra; Aarno Palotie; Munro Peacock; Nancy L. Pedersen; Paolo Peterlongo; Julian Peto; Paul D. P. Pharoah; Dirkje S. Postma; Anneli Pouta; Katri Pylkaes; Paolo Radice; Susan Ring; Fernando Rivadeneira; Antonietta Robino; Lynda M. Rose; Anja Rudolph; Veikko Salomaa; Serena Sanna; David Schlessinger; Marjanka K. Schmidt; Mellissa C. Southey; Ulla Sovio; Meir J. Stampfer; Doris Stoeckl; Anna M. Storniolo; Nicholas J. Timpson; Jonathan Tyrer; Jenny A. Visser; Peter Vollenweider; Henry Voelzke; Gerard Waeber; Melanie Waldenberger; Henri Wallaschofski; Qin Wang; Gonneke Willemsen; Robert Winqvist; Bruce H. R. Wolffenbuttel; Margaret J. Wright; Dorret I. Boomsma; Michael J. Econs; Kay-Tee Khaw; Ruth J. F. Loos; Mark I. McCarthy; Grant W. Montgomery; John P. Rice; Elizabeth A. Streeten; Unnur Thorsteinsdottir; Cornelia M. van Duijn; Behrooz Z. Alizadeh; Sven Bergmann; Eric Boerwinkle; Heather A. Boyd; Laura Crisponi; Paolo Gasparini; Christian Gieger; Tamara B. Harris; Erik Ingelsson; Marjo-Riitta Jaervelin; Peter Kraft; Debbie Lawlor; Andres Metspalu; Craig E. Pennell; Paul M. Ridker; Harold Snieder; Thorkild I. A. Sorensen; Tim D. Spector; David P. Strachan; Andre G. Uitterlinden; Nicholas J. Wareham; Elisabeth Widen; Marek Zygmunt; Anna Murray; Douglas F. Easton; Kari Stefansson; Joanne M. Murabito; Ken K. Ong; Australian Ovarian Canc Study; GENICA Network; kConFabt LifeLines Cohort Study; InterAct Consortium; Early Growth Genetics EGG Consorti

doi:10.1038/nature13545

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R. B. Perry^*, Felix Day, Cathy E. Elks, Patrick Sulem, Deborah J. Thompson, Teresa Ferreira, Chunyan He, Daniel I. Chasman, Toenu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q. Ang, Tanguy Corre, Diana L. Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D. Johnson, Sanela Kjellqvist, Kathryn L. LunettaGeorge McMahon, Ilja M. Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V. Smith, Lisette Stolk, Alexander Teumer, Natalia Tsernikova, Emmi Tikkanen, Sheila Ulivi, Erin K. Wagner, Najaf Amin, Laura J. Bierut, Enda M. Byrne, Jouke-Jan Hottenga, Daniel L. Koller, Massimo Mangino, Tune Hannes Pers, Laura M. Yerges-Armstrong, Jing Hua Zhao, Irene L. Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W. Beckmann, Javier Benitez, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E. Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J. Margriet Collee, Fergus J. Couch, David Couper, Andrea D. Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Peter Devilee, Aida K. Dieffenbach, Alison M. Dunning, Gudny Eiriksdottir, Johan G. Eriksson, Peter A. Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E. Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E. J. de Geus, Graham G. Giles, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pascal Guenel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A. Hartman, AndrewC Heath, Albert Hofman, Maartje J. Hooning, John L. Hopper, Frank B. Hu, David J. Hunter, David Karasik, Douglas P. Kiel, Julia A. Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Maegi, Patrik K. Magnusson, Arto Mannermaa, Nicholas G. Martin, Gisli Masson, Patrick F. McArdle, Wendy L. McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L. Milne, Heli Nevanlinna, Patrick Neven, Ellen A. Nohr, Albertine J. Oldehinkel, Ben A. Oostra, Aarno Palotie, Munro Peacock, Nancy L. Pedersen, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Dirkje S. Postma, Anneli Pouta, Katri Pylkaes, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M. Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K. Schmidt, Mellissa C. Southey, Ulla Sovio, Meir J. Stampfer, Doris Stoeckl, Anna M. Storniolo, Nicholas J. Timpson, Jonathan Tyrer, Jenny A. Visser, Peter Vollenweider, Henry Voelzke, Gerard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H. R. Wolffenbuttel, Margaret J. Wright, Dorret I. Boomsma, Michael J. Econs, Kay-Tee Khaw, Ruth J. F. Loos, Mark I. McCarthy, Grant W. Montgomery, John P. Rice, Elizabeth A. Streeten, Unnur Thorsteinsdottir, Cornelia M. van Duijn, Behrooz Z. Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A. Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B. Harris, Erik Ingelsson, Marjo-Riitta Jaervelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Harold Snieder, Thorkild I. A. Sorensen, Tim D. Spector, David P. Strachan, Andre G. Uitterlinden, Nicholas J. Wareham, Elisabeth Widen, Marek Zygmunt, Anna Murray, Douglas F. Easton, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, Australian Ovarian Canc Study, GENICA Network, kConFabt LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics EGG Consorti

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P <5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Original language	English
Journal	Nature
Volume	514
Issue number	7520
Pages (from-to)	92-97
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature13545
Publication status	Published - 2014

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Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., Corre, T., Cousminer, D. L., Feenstra, B., Franceschini, N., Ganna, A., Johnson, A. D., Kjellqvist, S., ... Consorti, E. G. G. EGG. (2014). Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature, 514(7520), 92-97. https://doi.org/10.1038/nature13545

@article{e683c7075dc94d8393ae5c7d29a32807,

title = "Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche",

abstract = "Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P <5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.",

author = "Perry, {John R. B.} and Felix Day and Elks, {Cathy E.} and Patrick Sulem and Thompson, {Deborah J.} and Teresa Ferreira and Chunyan He and Chasman, {Daniel I.} and Toenu Esko and Gudmar Thorleifsson and Eva Albrecht and Ang, {Wei Q.} and Tanguy Corre and Cousminer, {Diana L.} and Bjarke Feenstra and Nora Franceschini and Andrea Ganna and Johnson, {Andrew D.} and Sanela Kjellqvist and Lunetta, {Kathryn L.} and George McMahon and Nolte, {Ilja M.} and Lavinia Paternoster and Eleonora Porcu and Smith, {Albert V.} and Lisette Stolk and Alexander Teumer and Natalia Tsernikova and Emmi Tikkanen and Sheila Ulivi and Wagner, {Erin K.} and Najaf Amin and Bierut, {Laura J.} and Byrne, {Enda M.} and Jouke-Jan Hottenga and Koller, {Daniel L.} and Massimo Mangino and Pers, {Tune Hannes} and Yerges-Armstrong, {Laura M.} and Zhao, {Jing Hua} and Andrulis, {Irene L.} and Hoda Anton-Culver and Femke Atsma and Stefania Bandinelli and Beckmann, {Matthias W.} and Javier Benitez and Carl Blomqvist and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Bernardo Bonanni and Hiltrud Brauch and Hermann Brenner and Buring, {Julie E.} and Jenny Chang-Claude and Stephen Chanock and Jinhui Chen and Georgia Chenevix-Trench and Collee, {J. Margriet} and Couch, {Fergus J.} and David Couper and Coviello, {Andrea D.} and Angela Cox and Kamila Czene and D'adamo, {Adamo Pio} and Smith, {George Davey} and {De Vivo}, Immaculata and Demerath, {Ellen W.} and Joe Dennis and Peter Devilee and Dieffenbach, {Aida K.} and Dunning, {Alison M.} and Gudny Eiriksdottir and Eriksson, {Johan G.} and Fasching, {Peter A.} and Luigi Ferrucci and Dieter Flesch-Janys and Henrik Flyger and Tatiana Foroud and Lude Franke and Garcia, {Melissa E.} and Montserrat Garcia-Closas and Frank Geller and {de Geus}, {Eco E. J.} and Giles, {Graham G.} and Gudbjartsson, {Daniel F.} and Vilmundur Gudnason and Pascal Guenel and Suiqun Guo and Per Hall and Ute Hamann and Robin Haring and Hartman, {Catharina A.} and AndrewC Heath and Albert Hofman and Hooning, {Maartje J.} and Hopper, {John L.} and Hu, {Frank B.} and Hunter, {David J.} and David Karasik and Kiel, {Douglas P.} and Knight, {Julia A.} and Veli-Matti Kosma and Zoltan Kutalik and Sandra Lai and Diether Lambrechts and Annika Lindblom and Reedik Maegi and Magnusson, {Patrik K.} and Arto Mannermaa and Martin, {Nicholas G.} and Gisli Masson and McArdle, {Patrick F.} and McArdle, {Wendy L.} and Mads Melbye and Kyriaki Michailidou and Evelin Mihailov and Lili Milani and Milne, {Roger L.} and Heli Nevanlinna and Patrick Neven and Nohr, {Ellen A.} and Oldehinkel, {Albertine J.} and Oostra, {Ben A.} and Aarno Palotie and Munro Peacock and Pedersen, {Nancy L.} and Paolo Peterlongo and Julian Peto and Pharoah, {Paul D. P.} and Postma, {Dirkje S.} and Anneli Pouta and Katri Pylkaes and Paolo Radice and Susan Ring and Fernando Rivadeneira and Antonietta Robino and Rose, {Lynda M.} and Anja Rudolph and Veikko Salomaa and Serena Sanna and David Schlessinger and Schmidt, {Marjanka K.} and Southey, {Mellissa C.} and Ulla Sovio and Stampfer, {Meir J.} and Doris Stoeckl and Storniolo, {Anna M.} and Timpson, {Nicholas J.} and Jonathan Tyrer and Visser, {Jenny A.} and Peter Vollenweider and Henry Voelzke and Gerard Waeber and Melanie Waldenberger and Henri Wallaschofski and Qin Wang and Gonneke Willemsen and Robert Winqvist and Wolffenbuttel, {Bruce H. R.} and Wright, {Margaret J.} and Boomsma, {Dorret I.} and Econs, {Michael J.} and Kay-Tee Khaw and Loos, {Ruth J. F.} and McCarthy, {Mark I.} and Montgomery, {Grant W.} and Rice, {John P.} and Streeten, {Elizabeth A.} and Unnur Thorsteinsdottir and {van Duijn}, {Cornelia M.} and Alizadeh, {Behrooz Z.} and Sven Bergmann and Eric Boerwinkle and Boyd, {Heather A.} and Laura Crisponi and Paolo Gasparini and Christian Gieger and Harris, {Tamara B.} and Erik Ingelsson and Marjo-Riitta Jaervelin and Peter Kraft and Debbie Lawlor and Andres Metspalu and Pennell, {Craig E.} and Ridker, {Paul M.} and Harold Snieder and Sorensen, {Thorkild I. A.} and Spector, {Tim D.} and Strachan, {David P.} and Uitterlinden, {Andre G.} and Wareham, {Nicholas J.} and Elisabeth Widen and Marek Zygmunt and Anna Murray and Easton, {Douglas F.} and Kari Stefansson and Murabito, {Joanne M.} and Ong, {Ken K.} and Study, {Australian Ovarian Canc} and GENICA Network and Study, {kConFabt LifeLines Cohort} and InterAct Consortium and Consorti, {Early Growth Genetics EGG}",

year = "2014",

doi = "10.1038/nature13545",

language = "English",

volume = "514",

pages = "92--97",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7520",

}

Perry, JRB, Day, F, Elks, CE, Sulem, P, Thompson, DJ, Ferreira, T, He, C, Chasman, DI, Esko, T, Thorleifsson, G, Albrecht, E, Ang, WQ, Corre, T, Cousminer, DL, Feenstra, B, Franceschini, N, Ganna, A, Johnson, AD, Kjellqvist, S, Lunetta, KL, McMahon, G, Nolte, IM, Paternoster, L, Porcu, E, Smith, AV, Stolk, L, Teumer, A, Tsernikova, N, Tikkanen, E, Ulivi, S, Wagner, EK, Amin, N, Bierut, LJ, Byrne, EM, Hottenga, J-J, Koller, DL, Mangino, M, Pers, TH, Yerges-Armstrong, LM, Zhao, JH, Andrulis, IL, Anton-Culver, H, Atsma, F, Bandinelli, S, Beckmann, MW, Benitez, J, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Buring, JE, Chang-Claude, J, Chanock, S, Chen, J, Chenevix-Trench, G, Collee, JM, Couch, FJ, Couper, D, Coviello, AD, Cox, A, Czene, K, D'adamo, AP, Smith, GD, De Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dieffenbach, AK, Dunning, AM, Eiriksdottir, G, Eriksson, JG, Fasching, PA, Ferrucci, L, Flesch-Janys, D, Flyger, H, Foroud, T, Franke, L, Garcia, ME, Garcia-Closas, M, Geller, F, de Geus, EEJ, Giles, GG, Gudbjartsson, DF, Gudnason, V, Guenel, P, Guo, S, Hall, P, Hamann, U, Haring, R, Hartman, CA, Heath, A, Hofman, A, Hooning, MJ, Hopper, JL, Hu, FB, Hunter, DJ, Karasik, D, Kiel, DP, Knight, JA, Kosma, V-M, Kutalik, Z, Lai, S, Lambrechts, D, Lindblom, A, Maegi, R, Magnusson, PK, Mannermaa, A, Martin, NG, Masson, G, McArdle, PF, McArdle, WL, Melbye, M, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Nevanlinna, H, Neven, P, Nohr, EA, Oldehinkel, AJ, Oostra, BA, Palotie, A, Peacock, M, Pedersen, NL, Peterlongo, P, Peto, J, Pharoah, PDP, Postma, DS, Pouta, A, Pylkaes, K, Radice, P, Ring, S, Rivadeneira, F, Robino, A, Rose, LM, Rudolph, A, Salomaa, V, Sanna, S, Schlessinger, D, Schmidt, MK, Southey, MC, Sovio, U, Stampfer, MJ, Stoeckl, D, Storniolo, AM, Timpson, NJ, Tyrer, J, Visser, JA, Vollenweider, P, Voelzke, H, Waeber, G, Waldenberger, M, Wallaschofski, H, Wang, Q, Willemsen, G, Winqvist, R, Wolffenbuttel, BHR, Wright, MJ, Boomsma, DI, Econs, MJ, Khaw, K-T, Loos, RJF, McCarthy, MI, Montgomery, GW, Rice, JP, Streeten, EA, Thorsteinsdottir, U, van Duijn, CM, Alizadeh, BZ, Bergmann, S, Boerwinkle, E, Boyd, HA, Crisponi, L, Gasparini, P, Gieger, C, Harris, TB, Ingelsson, E, Jaervelin, M-R, Kraft, P, Lawlor, D, Metspalu, A, Pennell, CE, Ridker, PM, Snieder, H, Sorensen, TIA, Spector, TD, Strachan, DP, Uitterlinden, AG, Wareham, NJ, Widen, E, Zygmunt, M, Murray, A, Easton, DF, Stefansson, K, Murabito, JM, Ong, KK, Study, AOC, Network, GENICA, Study, KCLC, Consortium, I & Consorti, EGGEGG 2014, 'Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche', Nature, vol. 514, no. 7520, pp. 92-97. https://doi.org/10.1038/nature13545

TY - JOUR

T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

AU - Perry, John R. B.

AU - Day, Felix

AU - Elks, Cathy E.

AU - Sulem, Patrick

AU - Thompson, Deborah J.

AU - Ferreira, Teresa

AU - He, Chunyan

AU - Chasman, Daniel I.

AU - Esko, Toenu

AU - Thorleifsson, Gudmar

AU - Albrecht, Eva

AU - Ang, Wei Q.

AU - Corre, Tanguy

AU - Cousminer, Diana L.

AU - Feenstra, Bjarke

AU - Franceschini, Nora

AU - Ganna, Andrea

AU - Johnson, Andrew D.

AU - Kjellqvist, Sanela

AU - Lunetta, Kathryn L.

AU - McMahon, George

AU - Nolte, Ilja M.

AU - Paternoster, Lavinia

AU - Porcu, Eleonora

AU - Smith, Albert V.

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Tsernikova, Natalia

AU - Tikkanen, Emmi

AU - Ulivi, Sheila

AU - Wagner, Erin K.

AU - Amin, Najaf

AU - Bierut, Laura J.

AU - Byrne, Enda M.

AU - Hottenga, Jouke-Jan

AU - Koller, Daniel L.

AU - Mangino, Massimo

AU - Pers, Tune Hannes

AU - Yerges-Armstrong, Laura M.

AU - Zhao, Jing Hua

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Atsma, Femke

AU - Bandinelli, Stefania

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Blomqvist, Carl

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Bonanni, Bernardo

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Buring, Julie E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen

AU - Chen, Jinhui

AU - Chenevix-Trench, Georgia

AU - Collee, J. Margriet

AU - Couch, Fergus J.

AU - Couper, David

AU - Coviello, Andrea D.

AU - Cox, Angela

AU - Czene, Kamila

AU - D'adamo, Adamo Pio

AU - Smith, George Davey

AU - De Vivo, Immaculata

AU - Demerath, Ellen W.

AU - Dennis, Joe

AU - Devilee, Peter

AU - Dieffenbach, Aida K.

AU - Dunning, Alison M.

AU - Eiriksdottir, Gudny

AU - Eriksson, Johan G.

AU - Fasching, Peter A.

AU - Ferrucci, Luigi

AU - Flesch-Janys, Dieter

AU - Flyger, Henrik

AU - Foroud, Tatiana

AU - Franke, Lude

AU - Garcia, Melissa E.

AU - Garcia-Closas, Montserrat

AU - Geller, Frank

AU - de Geus, Eco E. J.

AU - Giles, Graham G.

AU - Gudbjartsson, Daniel F.

AU - Gudnason, Vilmundur

AU - Guenel, Pascal

AU - Guo, Suiqun

AU - Hall, Per

AU - Hamann, Ute

AU - Haring, Robin

AU - Hartman, Catharina A.

AU - Heath, AndrewC

AU - Hofman, Albert

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Hu, Frank B.

AU - Hunter, David J.

AU - Karasik, David

AU - Kiel, Douglas P.

AU - Knight, Julia A.

AU - Kosma, Veli-Matti

AU - Kutalik, Zoltan

AU - Lai, Sandra

AU - Lambrechts, Diether

AU - Lindblom, Annika

AU - Maegi, Reedik

AU - Magnusson, Patrik K.

AU - Mannermaa, Arto

AU - Martin, Nicholas G.

AU - Masson, Gisli

AU - McArdle, Patrick F.

AU - McArdle, Wendy L.

AU - Melbye, Mads

AU - Michailidou, Kyriaki

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Milne, Roger L.

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Nohr, Ellen A.

AU - Oldehinkel, Albertine J.

AU - Oostra, Ben A.

AU - Palotie, Aarno

AU - Peacock, Munro

AU - Pedersen, Nancy L.

AU - Peterlongo, Paolo

AU - Peto, Julian

AU - Pharoah, Paul D. P.

AU - Postma, Dirkje S.

AU - Pouta, Anneli

AU - Pylkaes, Katri

AU - Radice, Paolo

AU - Ring, Susan

AU - Rivadeneira, Fernando

AU - Robino, Antonietta

AU - Rose, Lynda M.

AU - Rudolph, Anja

AU - Salomaa, Veikko

AU - Sanna, Serena

AU - Schlessinger, David

AU - Schmidt, Marjanka K.

AU - Southey, Mellissa C.

AU - Sovio, Ulla

AU - Stampfer, Meir J.

AU - Stoeckl, Doris

AU - Storniolo, Anna M.

AU - Timpson, Nicholas J.

AU - Tyrer, Jonathan

AU - Visser, Jenny A.

AU - Vollenweider, Peter

AU - Voelzke, Henry

AU - Waeber, Gerard

AU - Waldenberger, Melanie

AU - Wallaschofski, Henri

AU - Wang, Qin

AU - Willemsen, Gonneke

AU - Winqvist, Robert

AU - Wolffenbuttel, Bruce H. R.

AU - Wright, Margaret J.

AU - Boomsma, Dorret I.

AU - Econs, Michael J.

AU - Khaw, Kay-Tee

AU - Loos, Ruth J. F.

AU - McCarthy, Mark I.

AU - Montgomery, Grant W.

AU - Rice, John P.

AU - Streeten, Elizabeth A.

AU - Thorsteinsdottir, Unnur

AU - van Duijn, Cornelia M.

AU - Alizadeh, Behrooz Z.

AU - Bergmann, Sven

AU - Boerwinkle, Eric

AU - Boyd, Heather A.

AU - Crisponi, Laura

AU - Gasparini, Paolo

AU - Gieger, Christian

AU - Harris, Tamara B.

AU - Ingelsson, Erik

AU - Jaervelin, Marjo-Riitta

AU - Kraft, Peter

AU - Lawlor, Debbie

AU - Metspalu, Andres

AU - Pennell, Craig E.

AU - Ridker, Paul M.

AU - Snieder, Harold

AU - Sorensen, Thorkild I. A.

AU - Spector, Tim D.

AU - Strachan, David P.

AU - Uitterlinden, Andre G.

AU - Wareham, Nicholas J.

AU - Widen, Elisabeth

AU - Zygmunt, Marek

AU - Murray, Anna

AU - Easton, Douglas F.

AU - Stefansson, Kari

AU - Murabito, Joanne M.

AU - Ong, Ken K.

AU - Study, Australian Ovarian Canc

AU - Network, GENICA

AU - Study, kConFabt LifeLines Cohort

AU - Consortium, InterAct

AU - Consorti, Early Growth Genetics EGG

PY - 2014

Y1 - 2014

N2 - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P <5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

AB - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P <5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

U2 - 10.1038/nature13545

DO - 10.1038/nature13545

M3 - Journal article

C2 - 25231870

SN - 0028-0836

VL - 514

SP - 92

EP - 97

JO - Nature

JF - Nature

IS - 7520

ER -

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

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