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

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, Tsernikova 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 M, 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, Collee 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 P, Ferrucci L, Flesch-Janys D, Flyger H, Foroud T, Franke L, Garcia ME, Garcia-Closas M, Geller F, De Geus EEJ, Giles GG, Gudbjartsson DF, Gudnason V, Guenel P, Guo S, Hall P, Hamann U, Haring R, Hartman CA, Heath A, 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, Maegi 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, Pylkaes 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, Stoeckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider P, Voelzke 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, Jaervelin MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sorensen TIA, Spector TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton DF, Stefansson K, Murabito JM, Ong KK (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 514

Pages Range: 92-7

Journal Issue: 7520

DOI: 10.1038/nature13545

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 ?-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.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) deCODE genetics Iceland (IS) University of Oxford United Kingdom (GB) Indiana University United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) University of Tartu Estonia (EE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) University of Western Australia (UWA) Australia (AU) Université de Lausanne (UNIL) Switzerland (CH) Helsingin yliopisto / University of Helsinki Finland (FI) Statens Serum Institut Denmark (DK) University of North Carolina at Chapel Hill United States (USA) (US) Karolinska Institute Sweden (SE) US National Institutes of Health (NIH) United States (USA) (US) University of Bristol United Kingdom (GB) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy Italy (IT) Icelandic Heart Association (IHA) Iceland (IS) Erasmus University Medical Center (MC) Netherlands (NL) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) IRCCS Ospedale Infantile Burlo Garofolo Italy (IT) Washington University United States (USA) (US) University of Queensland Australia (AU) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) King’s College London United Kingdom (GB) Boston Children's Hospital United States (USA) (US) University of Maryland United States (USA) (US) Mount Sinai Hospital (MSH) Canada (CA) Tuscany Regional Health Agency Italy (IT) National Cancer Institute (NCI) United States (USA) (US) Boston University United States (USA) (US) Harvard University United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Sanquin Bloedbank Nijmegen Germany (DE) National Institute for Health and Welfare (THL) Finland (FI) Southern Medical University / 南方医科大学 China (CN) Massachusetts Institute of Technology (MIT) United States (USA) (US) Hebrew SeniorLife United States (USA) (US) University College London (UCL) United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University of Southern Denmark / Syddansk Universitet Denmark (DK) Oulun Yliopisto / University of Oulo Finland (FI) The University of Melbourne Australia (AU) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Netherlands Consortium for Healthy Ageing (NCHA) Netherlands (NL) University of Houston United States (USA) (US) Uppsala University Sweden (SE) University of Copenhagen Denmark (DK) University of Exeter United Kingdom (GB) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Leiden University Netherlands (NL) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Copenhagen University Hospital Denmark (DK) Antoni van Leeuwenhoek Netherlands (NL) University of Eastern Finland Finland (FI) Robert-Bosch-Krankenhaus Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Cancer Council Victoria Australia (AU) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) University of Sheffield United Kingdom (GB) University of California Irvine United States (USA) (US) Mayo Clinic United States (USA) (US)

How to cite

APA:

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), 92-7. https://dx.doi.org/10.1038/nature13545

MLA:

Perry, John R. B., et al. "Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche." Nature 514.7520 (2014): 92-7.

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