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 language | English (US) |
|---|---|
| Pages (from-to) | 92-97 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 514 |
| Issue number | 7520 |
| DOIs | |
| State | Published - Oct 2 2014 |
ASJC Scopus subject areas
- General
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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 journal › Article › peer-review
}
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
AU - Nolte, Ilja M.
AU - Paternoster, Lavinia
AU - Porcu, Eleonora
AU - Smith, Albert V.
AU - Stolk, Lisette
AU - Teumer, Alexander
AU - Tšernikova, 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 H.
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 - Collée, 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 - García-Closas, Montserrat
AU - Geller, Frank
AU - De Geus, Eco E.J.
AU - Giles, Graham G.
AU - Gudbjartsson, Daniel F.
AU - Gudnason, Vilmundur
AU - Guénel, Pascal
AU - Guo, Suiqun
AU - Hall, Per
AU - Hamann, Ute
AU - Haring, Robin
AU - Hartman, Catharina A.
AU - Heath, Andrew C.
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 - Mägi, 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 - Pylkäs, 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 - Stöckl, Doris
AU - Storniolo, Anna M.
AU - Timpson, Nicholas J.
AU - Tyrer, Jonathan
AU - Visser, Jenny A.
AU - Vollenweider, Peter
AU - Völzke, 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 - Järvelin, Marjo Riitta
AU - Kraft, Peter
AU - Lawlor, Debbie
AU - Metspalu, Andres
AU - Pennell, Craig E.
AU - Ridker, Paul M.
AU - Snieder, Harold
AU - Sørensen, Thorkild I.A.
AU - Spector, Tim D.
AU - Strachan, David P.
AU - Uitterlinden, André 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.
N1 - Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.
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
C2 - 25231870
AN - SCOPUS:84908024873
VL - 514
SP - 92
EP - 97
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7520
ER -