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DOI: 10.1038/nature13545
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
John R. B. Perry,Felix R. Day,Cathy E. Elks,Patrick Sulem,Deborah J. Thompson,Teresa Ferreira,Chunyan He,Daniel I. Chasman,Tõnu Esko,Guðmar Þorleifsson,Eva Albrecht,Wei 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 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 Benı́tez,Carl Blomqvist,Stig E. Bojesen,Manjeet K. Bolla,Bernardo Bonanni,Hiltrud Brauch,Hermann Brenner,Julie E. Buring,Jenny Chang‐Claude,Stephen J. Chanock,Jinhui Chen,Georgia Chenevix-Trench,J. Margriet Collée,Fergus J. Couch,David J. Couper,Andrea D. Coviello,Angela Cox,Kamila Czene,Pio D’Adamo,George Davey Smith,Immaculata De Vivo,Ellen W. Demerath,Joe Dennis,Peter Devilee,Aida Karina Dieffenbach,Alison M. Dunning,Guðný Eiríksdóttir,Johan G. Eriksson,Peter A. Fasching,Luigi Ferrucci,Dieter Flesch‐Janys,Henrik Flyger,Tatiana Foroud,Lude Franke,Melissa García,Montserrat García‐Closas,Frank Geller,Eco J. C. de Geus,Graham G. Giles,Daníel F. Guðbjartsson,Vilmundur Gudnason,Pascal Guénel,Suiqun Guo,Per Hall,Ute Hamann,R. Häring,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,Zoltán Kutalik,Sandra Lai,Diether Lambrechts,Annika Lindblom,Reedik Mägi,Patrik K. E. Magnusson,Arto Mannermaa,Nicholas G. Martin,Gísli Másson,Patrick F. McArdle,Wendy L. McArdle,Mads Melbye,Kyriaki Michailidou,Evelin Mihailov,Lili Milani,Roger L. Milne,Heli Nevanlinna,Patrick Neven,Ellen Aagaard Nøhr,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 M. Ring,Fernando Rivadeneira,Antonietta Robino,Lynda M. Rose,Anja Rudolph,Veikko Salomaa,Serena Sanna,David Schlessinger,Marjanka K. Schmidt,Melissa C. Southey,Ulla Sovio,Meir J. Stampfer,Doris Stöckl,Anna Maria Storniolo,Nicholas J. Timpson,Jonathan Tyrer,Jenny A. Visser,Péter Vollenweider,Henry Völzke,Gérard Waeber,Mélanie 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 Þorsteinsdóttir,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 A. 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 Widén,Marek Zygmunt,Anna Murray,Douglas F. Easton,Kāri Stefánsson,Joanne M. Murabito,Ken K. Ong
Menarche
Biology
Genome-wide association study
2014
Here 106 genomic loci associated with age at menarche, a marker of puberty timing in females, are identified; these loci show enrichment for genes involved in nuclear hormone receptor function, body mass index, and rare disorders of puberty, and for genes located in imprinted regions, with parent-of-origin specific effects at several loci. The age at which females first experience menstruation, called menarche, is a heritable trait associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and general mortality. This large-scale genome-wide association study identifies 123 signals at 106 genomic loci associated with age at menarche. New findings include parent-of-origin-specific allelic associations (both maternally and paternally driven) at three imprinted loci and the implication of retinoic acid and GABAB receptor II signalling and lysine-specific histone demethylation. These data bring new insights into the genetic architecture of puberty timing and suggest a model involving thousands of genetic variants. 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 mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, 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 × 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.
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“Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche” is a paper by John R. B. Perry Felix R. Day Cathy E. Elks Patrick Sulem Deborah J. Thompson Teresa Ferreira Chunyan He Daniel I. Chasman Tõnu Esko Guðmar Þorleifsson Eva Albrecht Wei 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 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 Benı́tez Carl Blomqvist Stig E. Bojesen Manjeet K. Bolla Bernardo Bonanni Hiltrud Brauch Hermann Brenner Julie E. Buring Jenny Chang‐Claude Stephen J. Chanock Jinhui Chen Georgia Chenevix-Trench J. Margriet Collée Fergus J. Couch David J. Couper Andrea D. Coviello Angela Cox Kamila Czene Pio D’Adamo George Davey Smith Immaculata De Vivo Ellen W. Demerath Joe Dennis Peter Devilee Aida Karina Dieffenbach Alison M. Dunning Guðný Eiríksdóttir Johan G. Eriksson Peter A. Fasching Luigi Ferrucci Dieter Flesch‐Janys Henrik Flyger Tatiana Foroud Lude Franke Melissa García Montserrat García‐Closas Frank Geller Eco J. C. de Geus Graham G. Giles Daníel F. Guðbjartsson Vilmundur Gudnason Pascal Guénel Suiqun Guo Per Hall Ute Hamann R. Häring 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 Zoltán Kutalik Sandra Lai Diether Lambrechts Annika Lindblom Reedik Mägi Patrik K. E. Magnusson Arto Mannermaa Nicholas G. Martin Gísli Másson Patrick F. McArdle Wendy L. McArdle Mads Melbye Kyriaki Michailidou Evelin Mihailov Lili Milani Roger L. Milne Heli Nevanlinna Patrick Neven Ellen Aagaard Nøhr 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 M. Ring Fernando Rivadeneira Antonietta Robino Lynda M. Rose Anja Rudolph Veikko Salomaa Serena Sanna David Schlessinger Marjanka K. Schmidt Melissa C. Southey Ulla Sovio Meir J. Stampfer Doris Stöckl Anna Maria Storniolo Nicholas J. Timpson Jonathan Tyrer Jenny A. Visser Péter Vollenweider Henry Völzke Gérard Waeber Mélanie 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 Þorsteinsdóttir 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 A. 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 Widén Marek Zygmunt Anna Murray Douglas F. Easton Kāri Stefánsson Joanne M. Murabito Ken K. Ong published in 2014. It has an Open Access status of “green”. You can read and download a PDF Full Text of this paper here.