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

John Rb 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; 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 Coveillo; 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 Ej 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 Dp 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 Hr Wolffenbuttel; Margaret J Wright; Dorret I Boomsma; Michael J Econs; Kay-Tee Khaw; Ruth Jf 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 Ia 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; InterAct Consortium; Panos Deloukas

doi:10.1038/nature13545

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

Journal article

Peer reviewed

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

John Rb Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tõnu Esko, Gudmar Thorleifsson, …

Nature (London), Vol.514(7520), pp.92-+

02/10/2014

DOI: https://doi.org/10.1038/nature13545

PMCID: PMC4185210

PMID: 25231870

Abstract

Adolescent

Age Factors

Alleles

Body Mass Index

Breast Neoplasms - genetics

Calcium-Binding Proteins

Cardiovascular Diseases - genetics

Child

Diabetes Mellitus, Type 2 - genetics

Europe - ethnology

Female

Genetic Loci - genetics

Genome-Wide Association Study

Genomic Imprinting - genetics

Humans

Hypothalamo-Hypophyseal System - physiology

Intercellular Signaling Peptides and Proteins - genetics

Male

Membrane Proteins - genetics

Menarche - genetics

Obesity - genetics

Ovary - physiology

Parents

Polymorphism, Single Nucleotide - genetics

Potassium Channels, Tandem Pore Domain - genetics

Proteins - genetics

Quantitative Trait Loci - genetics

Receptors, GABA-B - metabolism

Receptors, Retinoic Acid - metabolism

Ribonucleoproteins - genetics

Ubiquitin-Protein Ligases

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.

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Title: Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Creators - without role: John Rb Perry - King's College London
Felix Day - University of Cambridge
Cathy E Elks - University of Cambridge
Patrick Sulem - deCODE Genetics
Deborah J Thompson - University of Cambridge
Teresa Ferreira - University of Oxford
Chunyan He - Indiana University
Daniel I Chasman - Harvard Medical School
Tõnu Esko - Harvard Medical School
Gudmar Thorleifsson - deCODE Genetics
Eva Albrecht - Helmholtz Zentrum München
Wei Q Ang - University of Western Australia
Tanguy Corre - SIB Swiss Institute of Bioinformatics
Diana L Cousminer - University of Helsinki
Bjarke Feenstra - Statens Serum Institut
Nora Franceschini - Department of Epidemiology, University of North Carolina, Chapel Hill, NC
Andrea Ganna - Karolinska Institutet
Andrew D Johnson - Boston University
Sanela Kjellqvist - Karolinska Institutet
Kathryn L Lunetta - Boston University
George McMahon - University of Bristol
Ilja M Nolte - University Medical Center Groningen
Lavinia Paternoster - University of Bristol
Eleonora Porcu - University of Sassari
Albert V Smith - University of Iceland
Lisette Stolk - Genomics
Alexander Teumer - Genomics
Natalia Tšernikova - University of Tartu
Emmi Tikkanen - University of Helsinki
Sheila Ulivi - Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy
Erin K Wagner - Indiana University
Najaf Amin - Erasmus MC
Laura J Bierut - Dept. of Psychiatry, Washington University, St. Louis, MO 63110
Enda M Byrne - QIMR Berghofer Medical Research Institute
Jouke-Jan Hottenga - University of Amsterdam
Daniel L Koller - Indiana University
Massimo Mangino - King's College London
Tune H Pers - Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, Lyngby 2800, Denmark
Laura M Yerges-Armstrong - Genomic
Jing Hua Zhao - University of Cambridge
Irene L Andrulis - University of Toronto
Hoda Anton-Culver - University of California, Irvine
Femke Atsma - Sanquin
Stefania Bandinelli - Azienda Sanitaria di Firenze
Matthias W Beckmann - Friedrich-Alexander-Universität Erlangen-Nürnberg
Javier Benitez - Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
Carl Blomqvist - University of Helsinki
Stig E Bojesen - Copenhagen University Hospital
Manjeet K Bolla - University of Cambridge
Bernardo Bonanni - Mylan
Hiltrud Brauch - University of Tübingen
Hermann Brenner - Heidelberg
Julie E Buring - Harvard Medical School
Jenny Chang-Claude - Heidelberg
Stephen Chanock - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Jinhui Chen - Indiana University
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute
J Margriet Collée - Erasmus MC
Fergus J Couch - Mayo Clinic
David Couper - Department of Biostatistics, University of North Carolina, Chapel Hill, NC
Andrea D Coveillo - Boston University School of Medicine
Angela Cox - University of Sheffield
Kamila Czene - Karolinska Institutet
Adamo Pio D'adamo - University of Trieste
George Davey Smith - University of Bristol
Immaculata De Vivo - Brigham and Women's Hospital
Ellen W Demerath - University of Minnesota
Joe Dennis - University of Cambridge
Peter Devilee - Leiden University Medical Center
Aida K Dieffenbach - Heidelberg
Alison M Dunning - University of Cambridge
Gudny Eiriksdottir - Icelandic Heart Association
Johan G Eriksson - Folkhalsan Research Centre, Helsinki, Finland
Peter A Fasching - Friedrich-Alexander-Universität Erlangen-Nürnberg
Luigi Ferrucci - National Institute on Aging
Dieter Flesch-Janys - Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
Henrik Flyger - Copenhagen University Hospital
Tatiana Foroud - Indiana University
Lude Franke - University of Groningen
Melissa E Garcia - National Institutes of Health
Montserrat García-Closas - Korean Breast Cancer Society
Frank Geller - Statens Serum Institut
Eco Ej de Geus - EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands
Graham G Giles - University of Melbourne
Daniel F Gudbjartsson - University of Iceland
Vilmundur Gudnason - University of Iceland
Pascal Guénel - University of Paris-Sud
Suiqun Guo - Department of Obstetrics and Gynecology, Southern Medical University, Guangzhou, China
Per Hall - Karolinska Institutet
Ute Hamann - Heidelberg
Robin Haring - Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
Catharina A Hartman - University Medical Center Groningen
Andrew C Heath - Washington University, Department of Psychiatry, St.Louis, Missouri, USA
Albert Hofman - Erasmus MC
Maartje J Hooning - Erasmus MC
John L Hopper - University of Melbourne
Frank B Hu - Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
David J Hunter - Brigham and Women's Hospital
David Karasik - Hebrew SeniorLife
Douglas P Kiel - Beth Israel Deaconess Medical Center
Julia A Knight - University of Toronto
Veli-Matti Kosma - Kuopio University Hospital
Zoltan Kutalik - SIB Swiss Institute of Bioinformatics
Sandra Lai - Institute of Genetics
Diether Lambrechts - KU Leuven
Annika Lindblom - Karolinska Institutet
Reedik Mägi - University of Tartu
Patrik K Magnusson - Karolinska Institutet
Arto Mannermaa - Kuopio University Hospital
Nicholas G Martin - QIMR Berghofer Medical Research Institute
Gisli Masson - deCODE Genetics
Patrick F McArdle - Genomic
Wendy L McArdle - University of Bristol
Mads Melbye - Department of Medicine, Stanford School of Medicine, Stanford, USA
Kyriaki Michailidou - University of Cambridge
Evelin Mihailov - University of Tartu
Lili Milani - University of Tartu
Roger L Milne - University of Melbourne
Heli Nevanlinna - University of Helsinki
Patrick Neven - Breast Center
Ellen A Nohr - University of Southern Denmark
Albertine J Oldehinkel - University Medical Center Groningen
Ben A Oostra - Erasmus MC
Aarno Palotie - Massachusetts General Hospital
Munro Peacock - Indiana University
Nancy L Pedersen - Karolinska Institutet
Paolo Peterlongo - IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
Julian Peto - Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK
Paul Dp Pharoah - University of Cambridge
Dirkje S Postma - University Medical Center Groningen
Anneli Pouta - Oulu University Hospital
Katri Pylkäs - University of Oulu
Paolo Radice - Fondazione IRCCS Istituto Nazionale dei Tumori
Susan Ring - University of Bristol
Fernando Rivadeneira - Erasmus MC
Antonietta Robino - University of Trieste
Lynda M Rose - Brigham and Women's Hospital
Anja Rudolph - Heidelberg
Veikko Salomaa - National Institute for Health and Welfare, Finland
Serena Sanna - Institute of Genetics
David Schlessinger - National Institute on Aging
Marjanka K Schmidt - The Netherlands Cancer Institute
Mellissa C Southey - University of Melbourne
Ulla Sovio - University of Cambridge
Meir J Stampfer - Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
Doris Stöckl - Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians- University, Munich, Germany
Anna M Storniolo - Indiana University
Nicholas J Timpson - University of Bristol
Jonathan Tyrer - University of Cambridge
Jenny A Visser - Erasmus MC
Peter Vollenweider - University Hospital of Lausanne
Henry Völzke - DZHK (German Centre for Cardiovascular Research), partner site Greifswald, 17475 Greifswald, Germany
Gerard Waeber - University Hospital of Lausanne
Melanie Waldenberger - Helmholtz Zentrum München
Henri Wallaschofski - DZHK (German Centre for Cardiovascular Research), partner site Greifswald, 17475 Greifswald, Germany
Qin Wang - University of Cambridge
Gonneke Willemsen - University of Amsterdam
Robert Winqvist - University of Oulu
Bruce Hr Wolffenbuttel - University of Groningen
Margaret J Wright - Queensland Insitute of Medical Research, Brisbane, Queensland, Australia
Dorret I Boomsma - University of Amsterdam
Michael J Econs - Indiana University
Kay-Tee Khaw - University of Cambridge
Ruth Jf Loos - Icahn School of Medicine at Mount Sinai
Mark I McCarthy - University of Oxford
Grant W Montgomery - Queensland Insitute of Medical Research, Brisbane, Queensland, Australia
John P Rice - Dept. of Psychiatry, Washington University, St. Louis, MO 63110
Elizabeth A Streeten - Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, USA. Baltimore, MD 21201
Unnur Thorsteinsdottir - University of Iceland
Cornelia M van Duijn - Centre of Medical Systems Biology, Leiden, the Netherlands
Behrooz Z Alizadeh - University Medical Center Groningen
Sven Bergmann - SIB Swiss Institute of Bioinformatics
Eric Boerwinkle - University of Houston
Heather A Boyd - Statens Serum Institut
Laura Crisponi - Institute of Genetics
Paolo Gasparini - University of Trieste
Christian Gieger - Helmholtz Zentrum München
Tamara B Harris - National Institutes of Health
Erik Ingelsson - Uppsala University
Marjo-Riitta Järvelin - Oulu University Hospital
Peter Kraft - Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
Debbie Lawlor - University of Bristol
Andres Metspalu - University of Tartu
Craig E Pennell - University of Western Australia
Paul M Ridker - Harvard Medical School
Harold Snieder - University Medical Center Groningen
Thorkild Ia Sørensen - Capital University
Tim D Spector - King's College London
David P Strachan - St George's, University of London
André G Uitterlinden - Erasmus MC
Nicholas J Wareham - University of Cambridge
Elisabeth Widen - University of Helsinki
Marek Zygmunt - Department of Obstetrics and Gynecology, University Medicine Greifswald, 17475 Greifswald, Germany
Anna Murray - University of Exeter
Douglas F Easton - University of Cambridge
Kari Stefansson - University of Iceland
Joanne M Murabito - Boston University School of Medicine
Ken K Ong - University of Cambridge
InterAct Consortium
Panos Deloukas - King Abdulaziz University
Publication Details: Nature (London), Vol.514(7520), pp.92-+
Grant note: G0401527 / Medical Research Council P50 CA116201 / NCI NIH HHS G0701863 / Medical Research Council MC_UU_12015/1 / Medical Research Council U01 AG049505 / NIA NIH HHS 10119 / Cancer Research UK MC_U106179472 / Medical Research Council R01 NS017950 / NINDS NIH HHS MC_UU_12013/1 / Medical Research Council R01 AG041517 / NIA NIH HHS MR/J012165/1 / Medical Research Council MC_UU_12015/2 / Medical Research Council 098381 / Wellcome Trust UL1 TR001108 / NCATS NIH HHS 10124 / Cancer Research UK MC_U106179471 / Medical Research Council 10118 / Cancer Research UK MC_PC_15018 / Medical Research Council G9815508 / Medical Research Council 11022 / Cancer Research UK MC_UU_12013/3 / Medical Research Council 102215 / Wellcome Trust G1000143 / Medical Research Council
Identifiers: 9938693208331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article