Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2017-06

AUTHORS

Felix R Day, Deborah J Thompson, Hannes Helgason, Daniel I Chasman, Hilary Finucane, Patrick Sulem, Katherine S Ruth, Sean Whalen, Abhishek K Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina M Barbieri, Thibaud Boutin, Archie Campbell, Ellen Demerath, Ayush Giri, Chunyan He, Jouke J Hottenga, Robert Karlsson, Ivana Kolcic, Po-Ru Loh, Kathryn L Lunetta, Massimo Mangino, Brumat Marco, George McMahon, Sarah E Medland, Ilja M Nolte, Raymond Noordam, Teresa Nutile, Lavinia Paternoster, Natalia Perjakova, Eleonora Porcu, Lynda M Rose, Katharina E Schraut, Ayellet V Segrè, Albert V Smith, Lisette Stolk, Alexander Teumer, Irene L Andrulis, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E Bojesen, Manjeet K Bolla, Judith S Brand, Hiltrud Brauch, Hermann Brenner, Linda Broer, Thomas Brüning, Julie E Buring, Harry Campbell, Eulalia Catamo, Stephen Chanock, Georgia Chenevix-Trench, Tanguy Corre, Fergus J Couch, Diana L Cousminer, Angela Cox, Laura Crisponi, Kamila Czene, George Davey Smith, Eco J C N de Geus, Renée de Mutsert, Immaculata De Vivo, Joe Dennis, Peter Devilee, Isabel dos-Santos-Silva, Alison M Dunning, Johan G Eriksson, Peter A Fasching, Lindsay Fernández-Rhodes, Luigi Ferrucci, Dieter Flesch-Janys, Lude Franke, Marike Gabrielson, Ilaria Gandin, Graham G Giles, Harald Grallert, Daniel F Gudbjartsson, Pascal Guénel, Per Hall, Emily Hallberg, Ute Hamann, Tamara B Harris, Catharina A Hartman, Gerardo Heiss, Maartje J Hooning, John L Hopper, Frank Hu, David J Hunter, M Arfan Ikram, Hae Kyung Im, Marjo-Riitta Järvelin, Peter K Joshi, David Karasik, Manolis Kellis, Zoltan Kutalik, Genevieve LaChance, Diether Lambrechts, Claudia Langenberg, Lenore J Launer, Joop S E Laven, Stefania Lenarduzzi, Jingmei Li, Penelope A Lind, Sara Lindstrom, YongMei Liu, Jian'an Luan, Reedik Mägi, Arto Mannermaa, Hamdi Mbarek, Mark I McCarthy, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Kyriaki Michailidou, Lili Milani, Roger L Milne, Grant W Montgomery, Anna M Mulligan, Mike A Nalls, Pau Navarro, Heli Nevanlinna, Dale R Nyholt, Albertine J Oldehinkel, Tracy A O'Mara, Sandosh Padmanabhan, Aarno Palotie, Nancy Pedersen, Annette Peters, Julian Peto, Paul D P Pharoah, Anneli Pouta, Paolo Radice, Iffat Rahman, Susan M Ring, Antonietta Robino, Frits R Rosendaal, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F Sala, Marjanka K Schmidt, Robert A Scott, Mitul Shah, Rossella Sorice, Melissa C Southey, Ulla Sovio, Meir Stampfer, Maristella Steri, Konstantin Strauch, Toshiko Tanaka, Emmi Tikkanen, Nicholas J Timpson, Michela Traglia, Thérèse Truong, Jonathan P Tyrer, André G Uitterlinden, Digna R Velez Edwards, Veronique Vitart, Uwe Völker, Peter Vollenweider, Qin Wang, Elisabeth Widen, Ko Willems van Dijk, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Jing Hua Zhao, Magdalena Zoledziewska, Marek Zygmunt, Behrooz Z Alizadeh, Dorret I Boomsma, Marina Ciullo, Francesco Cucca, Tõnu Esko, Nora Franceschini, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Peter Kraft, Debbie A Lawlor, Patrik K E Magnusson, Nicholas G Martin, Dennis O Mook-Kanamori, Ellen A Nohr, Ozren Polasek, David Porteous, Alkes L Price, Paul M Ridker, Harold Snieder, Tim D Spector, Doris Stöckl, Daniela Toniolo, Sheila Ulivi, Jenny A Visser, Henry Völzke, Nicholas J Wareham, James F Wilson, The LifeLines Cohort Study, The InterAct Consortium, ConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Amanda B Spurdle, Unnur Thorsteindottir, Katherine S Pollard, Douglas F Easton, Joyce Y Tung, Jenny Chang-Claude, David Hinds, Anna Murray, Joanne M Murabito, Kari Stefansson, Ken K Ong, John R B Perry

ABSTRACT

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility. More... »

PAGES

834-841

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    6

    VOLUME

    49

    Author Affiliations

  • Institute of Metabolic Science
  • University of Cambridge
  • University of Iceland
  • Harvard University
  • Massachusetts Institute of Technology
  • University of Exeter
  • Gladstone Institutes
  • Broad Institute
  • University Medical Center Groningen
  • Vita-Salute San Raffaele University
  • University of Edinburgh
  • University of Minnesota
  • Vanderbilt University
  • Indiana University – Purdue University Indianapolis
  • VU University Amsterdam
  • Karolinska Institute
  • University of Split
  • Boston University
  • National Institute for Health Research
  • University of Trieste
  • University of Bristol
  • QIMR Berghofer Medical Research Institute
  • Leiden University Medical Center
  • Institute of Genetics and Biophysics
  • University of Tartu
  • National Research Council
  • Brigham and Women's Hospital
  • Icelandic Heart Association
  • Erasmus University Medical Center
  • University of Greifswald
  • University of Toronto
  • Azienda Sanitaria di Firenze
  • Spanish National Cancer Research Centre
  • University of Lausanne
  • Institute of Social and Preventive Medicine
  • The University of Texas Health Science Center at Houston
  • University of Copenhagen
  • German Cancer Research Center
  • Ruhr University Bochum
  • IRCCS Materno Infantile Burlo Garofolo
  • National Cancer Institute
  • Mayo Clinic
  • University of Pennsylvania
  • University of Sheffield
  • London School of Hygiene & Tropical Medicine
  • University of Helsinki
  • University of California Los Angeles
  • University of North Carolina at Chapel Hill
  • National Institute on Aging
  • University Medical Center Hamburg-Eppendorf
  • University of Melbourne
  • German Center for Diabetes Research
  • University of Paris-Sud
  • National Institutes of Health
  • Oulu University Hospital
  • King's College London
  • Flanders Institute for Biotechnology
  • University of Washington
  • Wake Forest University
  • Kuopio University Hospital
  • Wellcome Centre for Human Genetics
  • Augsburg Hospital
  • Cyprus Institute of Neurology and Genetics
  • University of Queensland
  • University Health Network
  • Queensland University of Technology
  • University of Glasgow
  • National Institute for Health and Welfare
  • Istituto Nazionale dei Tumori
  • Antoni van Leeuwenhoek Hospital
  • Ludwig Maximilian University of Munich
  • University Hospital of Lausanne
  • University of Oulu
  • University of Sassari
  • University of Southern Denmark
  • University of California, San Francisco
  • 23andMe (United States)
  • University Cancer Center Hamburg
  • Boston University School of Medicine
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.3841

    DOI

    http://dx.doi.org/10.1038/ng.3841

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1085051707

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28436984


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