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, Tõnu 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 & 178 others George McMahon, Ilja M. Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V. Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K. Wagner, Najaf Amin, Laura J. Bierut, Enda M. Byrne, Jouke Jan Hottenga, Daniel L. Koller, Massimo Mangino, Tune H. 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 Collée, 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 García-Closas, Frank Geller, Eco E J De Geus, Graham G. Giles, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A. Hartman, Andrew C. 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 Mägi, 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 Pylkäs, 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 Stöckl, Anna M. Storniolo, Nicholas J. Timpson, Jonathan Tyrer, Jenny A. Visser, Peter Vollenweider, Henry Völzke, 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 Järvelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D. Spector, David P. Strachan, André G. Uitterlinden, Nicholas J. Wareham, Elisabeth Widen, Marek Zygmunt, Anna Murray, Douglas F. Easton, Kari Stefansson, Joanne M. Murabito, Ken K. Ong

Research output: Contribution to journalArticle

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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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 languageEnglish (US)
Pages (from-to)92-97
Number of pages6
JournalNature
Volume514
Issue number7520
DOIs
StatePublished - Oct 2 2014
Externally publishedYes

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Menarche
Puberty
Aminobutyrates
Cytoplasmic and Nuclear Receptors
Rare Diseases
Tretinoin
Type 2 Diabetes Mellitus
Body Mass Index
Cardiovascular Diseases
Animal Models
Obesity
Genome
Breast Neoplasms
Mortality
Genes

ASJC Scopus subject areas

  • General

Cite this

Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., ... Ong, K. K. (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

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. / Perry, John R B; Day, Felix; Elks, Cathy E.; Sulem, Patrick; Thompson, Deborah J.; Ferreira, Teresa; He, Chunyan; Chasman, Daniel I.; Esko, Tõnu; Thorleifsson, Gudmar; Albrecht, Eva; Ang, Wei Q.; Corre, Tanguy; Cousminer, Diana L.; Feenstra, Bjarke; Franceschini, Nora; Ganna, Andrea; Johnson, Andrew D.; Kjellqvist, Sanela; Lunetta, Kathryn L.; McMahon, George; Nolte, Ilja M.; Paternoster, Lavinia; Porcu, Eleonora; Smith, Albert V.; Stolk, Lisette; Teumer, Alexander; Tšernikova, Natalia; Tikkanen, Emmi; Ulivi, Sheila; Wagner, Erin K.; Amin, Najaf; Bierut, Laura J.; Byrne, Enda M.; Hottenga, Jouke Jan; Koller, Daniel L.; Mangino, Massimo; Pers, Tune H.; Yerges-Armstrong, Laura M.; Zhao, Jing Hua; Andrulis, Irene L.; Anton-Culver, Hoda; Atsma, Femke; Bandinelli, Stefania; Beckmann, Matthias W.; Benitez, Javier; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Buring, Julie E.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Jinhui; Chenevix-Trench, Georgia; Collée, J. Margriet; Couch, Fergus J.; Couper, David; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; D'adamo, Adamo Pio; Smith, George Davey; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dieffenbach, Aida K.; Dunning, Alison M.; Eiriksdottir, Gudny; Eriksson, Johan G.; Fasching, Peter A.; Ferrucci, Luigi; Flesch-Janys, Dieter; Flyger, Henrik; Foroud, Tatiana; Franke, Lude; Garcia, Melissa E.; García-Closas, Montserrat; Geller, Frank; De Geus, Eco E J; Giles, Graham G.; Gudbjartsson, Daniel F.; Gudnason, Vilmundur; Guénel, Pascal; Guo, Suiqun; Hall, Per; Hamann, Ute; Haring, Robin; Hartman, Catharina A.; Heath, Andrew C.; Hofman, Albert; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Hunter, David J.; Karasik, David; Kiel, Douglas P.; Knight, Julia A.; Kosma, Veli Matti; Kutalik, Zoltan; Lai, Sandra; Lambrechts, Diether; Lindblom, Annika; Mägi, Reedik; Magnusson, Patrik K.; Mannermaa, Arto; Martin, Nicholas G.; Masson, Gisli; McArdle, Patrick F.; McArdle, Wendy L.; Melbye, Mads; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Nevanlinna, Heli; Neven, Patrick; Nohr, Ellen A.; Oldehinkel, Albertine J.; Oostra, Ben A.; Palotie, Aarno; Peacock, Munro; Pedersen, Nancy L.; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D P; Postma, Dirkje S.; Pouta, Anneli; Pylkäs, Katri; Radice, Paolo; Ring, Susan; Rivadeneira, Fernando; Robino, Antonietta; Rose, Lynda M.; Rudolph, Anja; Salomaa, Veikko; Sanna, Serena; Schlessinger, David; Schmidt, Marjanka K.; Southey, Mellissa C.; Sovio, Ulla; Stampfer, Meir J.; Stöckl, Doris; Storniolo, Anna M.; Timpson, Nicholas J.; Tyrer, Jonathan; Visser, Jenny A.; Vollenweider, Peter; Völzke, Henry; Waeber, Gerard; Waldenberger, Melanie; Wallaschofski, Henri; Wang, Qin; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce H R; Wright, Margaret J.; Boomsma, Dorret I.; Econs, Michael J.; Khaw, Kay Tee; Loos, Ruth J F; McCarthy, Mark I.; Montgomery, Grant W.; Rice, John P.; Streeten, Elizabeth A.; Thorsteinsdottir, Unnur; Van Duijn, Cornelia M.; Alizadeh, Behrooz Z.; Bergmann, Sven; Boerwinkle, Eric; Boyd, Heather A.; Crisponi, Laura; Gasparini, Paolo; Gieger, Christian; Harris, Tamara B.; Ingelsson, Erik; Järvelin, Marjo Riitta; Kraft, Peter; Lawlor, Debbie; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Snieder, Harold; Sørensen, Thorkild I A; Spector, Tim D.; Strachan, David P.; Uitterlinden, André G.; Wareham, Nicholas J.; Widen, Elisabeth; Zygmunt, Marek; Murray, Anna; Easton, Douglas F.; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.

In: Nature, Vol. 514, No. 7520, 02.10.2014, p. 92-97.

Research output: Contribution to journalArticle

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, Tšernikova, N, Tikkanen, E, Ulivi, S, Wagner, EK, Amin, N, Bierut, LJ, Byrne, EM, Hottenga, JJ, 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, Collée, 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, García-Closas, M, Geller, F, De Geus, EEJ, Giles, GG, Gudbjartsson, DF, Gudnason, V, Guénel, P, Guo, S, Hall, P, Hamann, U, Haring, R, Hartman, CA, Heath, AC, Hofman, A, Hooning, MJ, Hopper, JL, Hu, FB, Hunter, DJ, Karasik, D, Kiel, DP, Knight, JA, Kosma, VM, Kutalik, Z, Lai, S, Lambrechts, D, Lindblom, A, Mägi, 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, Pylkäs, 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, Stöckl, D, Storniolo, AM, Timpson, NJ, Tyrer, J, Visser, JA, Vollenweider, P, Völzke, H, Waeber, G, Waldenberger, M, Wallaschofski, H, Wang, Q, Willemsen, G, Winqvist, R, Wolffenbuttel, BHR, Wright, MJ, Boomsma, DI, Econs, MJ, Khaw, KT, 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, Järvelin, MR, Kraft, P, Lawlor, D, Metspalu, A, Pennell, CE, Ridker, PM, Snieder, H, Sørensen, TIA, Spector, TD, Strachan, DP, Uitterlinden, AG, Wareham, NJ, Widen, E, Zygmunt, M, Murray, A, Easton, DF, Stefansson, K, Murabito, JM & Ong, KK 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
Perry JRB, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014 Oct 2;514(7520):92-97. https://doi.org/10.1038/nature13545
Perry, John R B ; Day, Felix ; Elks, Cathy E. ; Sulem, Patrick ; Thompson, Deborah J. ; Ferreira, Teresa ; He, Chunyan ; Chasman, Daniel I. ; Esko, Tõnu ; Thorleifsson, Gudmar ; Albrecht, Eva ; Ang, Wei Q. ; Corre, Tanguy ; Cousminer, Diana L. ; Feenstra, Bjarke ; Franceschini, Nora ; Ganna, Andrea ; Johnson, Andrew D. ; Kjellqvist, Sanela ; Lunetta, Kathryn L. ; McMahon, George ; Nolte, Ilja M. ; Paternoster, Lavinia ; Porcu, Eleonora ; Smith, Albert V. ; Stolk, Lisette ; Teumer, Alexander ; Tšernikova, Natalia ; Tikkanen, Emmi ; Ulivi, Sheila ; Wagner, Erin K. ; Amin, Najaf ; Bierut, Laura J. ; Byrne, Enda M. ; Hottenga, Jouke Jan ; Koller, Daniel L. ; Mangino, Massimo ; Pers, Tune H. ; Yerges-Armstrong, Laura M. ; Zhao, Jing Hua ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Atsma, Femke ; Bandinelli, Stefania ; Beckmann, Matthias W. ; Benitez, Javier ; Blomqvist, Carl ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Bonanni, Bernardo ; Brauch, Hiltrud ; Brenner, Hermann ; Buring, Julie E. ; Chang-Claude, Jenny ; Chanock, Stephen ; Chen, Jinhui ; Chenevix-Trench, Georgia ; Collée, J. Margriet ; Couch, Fergus J. ; Couper, David ; Coviello, Andrea D. ; Cox, Angela ; Czene, Kamila ; D'adamo, Adamo Pio ; Smith, George Davey ; De Vivo, Immaculata ; Demerath, Ellen W. ; Dennis, Joe ; Devilee, Peter ; Dieffenbach, Aida K. ; Dunning, Alison M. ; Eiriksdottir, Gudny ; Eriksson, Johan G. ; Fasching, Peter A. ; Ferrucci, Luigi ; Flesch-Janys, Dieter ; Flyger, Henrik ; Foroud, Tatiana ; Franke, Lude ; Garcia, Melissa E. ; García-Closas, Montserrat ; Geller, Frank ; De Geus, Eco E J ; Giles, Graham G. ; Gudbjartsson, Daniel F. ; Gudnason, Vilmundur ; Guénel, Pascal ; Guo, Suiqun ; Hall, Per ; Hamann, Ute ; Haring, Robin ; Hartman, Catharina A. ; Heath, Andrew C. ; Hofman, Albert ; Hooning, Maartje J. ; Hopper, John L. ; Hu, Frank B. ; Hunter, David J. ; Karasik, David ; Kiel, Douglas P. ; Knight, Julia A. ; Kosma, Veli Matti ; Kutalik, Zoltan ; Lai, Sandra ; Lambrechts, Diether ; Lindblom, Annika ; Mägi, Reedik ; Magnusson, Patrik K. ; Mannermaa, Arto ; Martin, Nicholas G. ; Masson, Gisli ; McArdle, Patrick F. ; McArdle, Wendy L. ; Melbye, Mads ; Michailidou, Kyriaki ; Mihailov, Evelin ; Milani, Lili ; Milne, Roger L. ; Nevanlinna, Heli ; Neven, Patrick ; Nohr, Ellen A. ; Oldehinkel, Albertine J. ; Oostra, Ben A. ; Palotie, Aarno ; Peacock, Munro ; Pedersen, Nancy L. ; Peterlongo, Paolo ; Peto, Julian ; Pharoah, Paul D P ; Postma, Dirkje S. ; Pouta, Anneli ; Pylkäs, Katri ; Radice, Paolo ; Ring, Susan ; Rivadeneira, Fernando ; Robino, Antonietta ; Rose, Lynda M. ; Rudolph, Anja ; Salomaa, Veikko ; Sanna, Serena ; Schlessinger, David ; Schmidt, Marjanka K. ; Southey, Mellissa C. ; Sovio, Ulla ; Stampfer, Meir J. ; Stöckl, Doris ; Storniolo, Anna M. ; Timpson, Nicholas J. ; Tyrer, Jonathan ; Visser, Jenny A. ; Vollenweider, Peter ; Völzke, Henry ; Waeber, Gerard ; Waldenberger, Melanie ; Wallaschofski, Henri ; Wang, Qin ; Willemsen, Gonneke ; Winqvist, Robert ; Wolffenbuttel, Bruce H R ; Wright, Margaret J. ; Boomsma, Dorret I. ; Econs, Michael J. ; Khaw, Kay Tee ; Loos, Ruth J F ; McCarthy, Mark I. ; Montgomery, Grant W. ; Rice, John P. ; Streeten, Elizabeth A. ; Thorsteinsdottir, Unnur ; Van Duijn, Cornelia M. ; Alizadeh, Behrooz Z. ; Bergmann, Sven ; Boerwinkle, Eric ; Boyd, Heather A. ; Crisponi, Laura ; Gasparini, Paolo ; Gieger, Christian ; Harris, Tamara B. ; Ingelsson, Erik ; Järvelin, Marjo Riitta ; Kraft, Peter ; Lawlor, Debbie ; Metspalu, Andres ; Pennell, Craig E. ; Ridker, Paul M. ; Snieder, Harold ; Sørensen, Thorkild I A ; Spector, Tim D. ; Strachan, David P. ; Uitterlinden, André G. ; Wareham, Nicholas J. ; Widen, Elisabeth ; Zygmunt, Marek ; Murray, Anna ; Easton, Douglas F. ; Stefansson, Kari ; Murabito, Joanne M. ; Ong, Ken K. / Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. In: Nature. 2014 ; Vol. 514, No. 7520. pp. 92-97.
@article{00881480a1b0464f8de0fd3ffd966666,
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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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 T{\~o}nu 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 Tšernikova and Emmi Tikkanen and Sheila Ulivi and Wagner, {Erin K.} and Najaf Amin and Bierut, {Laura J.} and Byrne, {Enda M.} and Hottenga, {Jouke Jan} and Koller, {Daniel L.} and Massimo Mangino and Pers, {Tune H.} 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 Coll{\'e}e, {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 Garc{\'i}a-Closas and Frank Geller and {De Geus}, {Eco E J} and Giles, {Graham G.} and Gudbjartsson, {Daniel F.} and Vilmundur Gudnason and Pascal Gu{\'e}nel and Suiqun Guo and Per Hall and Ute Hamann and Robin Haring and Hartman, {Catharina A.} and Heath, {Andrew C.} 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 Kosma, {Veli Matti} and Zoltan Kutalik and Sandra Lai and Diether Lambrechts and Annika Lindblom and Reedik M{\"a}gi 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 Pylk{\"a}s 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 St{\"o}ckl and Storniolo, {Anna M.} and Timpson, {Nicholas J.} and Jonathan Tyrer and Visser, {Jenny A.} and Peter Vollenweider and Henry V{\"o}lzke 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 Khaw, {Kay Tee} 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 J{\"a}rvelin, {Marjo Riitta} and Peter Kraft and Debbie Lawlor and Andres Metspalu and Pennell, {Craig E.} and Ridker, {Paul M.} and Harold Snieder and S{\o}rensen, {Thorkild I A} and Spector, {Tim D.} and Strachan, {David P.} and Uitterlinden, {Andr{\'e} 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.}",
year = "2014",
month = "10",
day = "2",
doi = "10.1038/nature13545",
language = "English (US)",
volume = "514",
pages = "92--97",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7520",

}

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, Tõnu

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

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AU - Ong, Ken K.

PY - 2014/10/2

Y1 - 2014/10/2

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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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.

UR - http://www.scopus.com/inward/record.url?scp=84908024873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908024873&partnerID=8YFLogxK

U2 - 10.1038/nature13545

DO - 10.1038/nature13545

M3 - Article

VL - 514

SP - 92

EP - 97

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7520

ER -