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

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 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 gamma-aminobutyric acid-B2 receptor signaling, 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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Item Type:	Article
Authors/Creators:	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, J-J Koller, DL Mangino, M Pers, TH Yerges-Armstrong, LM Zhao, JH Andrulis, IL Anton-Culver, H Atsma, F Bandinelli, S Beckmann, MW 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 https://orcid.org/0000-0002-5138-1099 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, PA 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, V-M 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, K-T 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, M-R 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 Study, AOC Network, GENICA Study, KLC Consortium, I Consorti, EGGEGG
Copyright, Publisher and Additional Information:	© 2014 Nature Publishing Group. This is an author produced version of a paper subsequently published in Nature. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: 2 October 2014
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	12 Dec 2016 16:48
Last Modified:	29 Mar 2018 07:43
Published Version:	http://doi.org/10.1038/nature13545
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/nature13545
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:107834

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

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