Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Abstract

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Metadata

Item Type:	Article
Authors/Creators:	Kentistou, K.A. https://orcid.org/0000-0002-5816-664X Kaisinger, L.R. https://orcid.org/0000-0002-0849-3191 Stankovic, S. https://orcid.org/0000-0002-6602-1379 Vaudel, M. https://orcid.org/0000-0003-1179-9578 Mendes de Oliveira, E. Messina, A. https://orcid.org/0000-0002-2393-1874 Walters, R.G. https://orcid.org/0000-0002-9179-0321 Liu, X. Busch, A.S. Helgason, H. Thompson, D.J. Santoni, F. https://orcid.org/0000-0002-3258-4747 Petricek, K.M. https://orcid.org/0000-0002-3352-093X Zouaghi, Y. Huang-Doran, I. Gudbjartsson, D.F. https://orcid.org/0000-0002-5222-9857 Bratland, E. Lin, K. Gardner, E.J. https://orcid.org/0000-0001-9671-1533 Zhao, Y. https://orcid.org/0000-0002-2747-0219 Jia, R.Y. Terao, C. https://orcid.org/0000-0002-6452-4095 Riggan, M.J. Bolla, M.K. Yazdanpanah, M. Yazdanpanah, N. Bradfield, J.P. Broer, L. https://orcid.org/0000-0003-0011-123X Campbell, A. https://orcid.org/0000-0003-0198-5078 Chasman, D.I. https://orcid.org/0000-0003-3357-0862 Cousminer, D.L. Franceschini, N. https://orcid.org/0009-0001-8346-3662 Franke, L.H. https://orcid.org/0000-0002-5159-8802 Girotto, G. https://orcid.org/0000-0003-4507-6589 He, C. Järvelin, M.-R. https://orcid.org/0000-0002-2149-0630 Joshi, P.K. Kamatani, Y. https://orcid.org/0000-0001-8748-5597 Karlsson, R. https://orcid.org/0000-0002-8949-2587 Luan, J. https://orcid.org/0000-0003-3137-6337 Lunetta, K.L. https://orcid.org/0000-0002-9268-810X Mägi, R. https://orcid.org/0000-0002-2964-6011 Mangino, M. https://orcid.org/0000-0002-2167-7470 Medland, S.E. https://orcid.org/0000-0003-1382-380X Meisinger, C. Noordam, R. https://orcid.org/0000-0001-7801-809X Nutile, T. Concas, M.P. https://orcid.org/0000-0003-3598-2537 Polašek, O. Porcu, E. 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Launer, L.J. https://orcid.org/0000-0002-3238-7612 Lind, P.A. https://orcid.org/0000-0002-3887-2598 Lindblom, A. Magnusson, P.K.E. https://orcid.org/0000-0002-7315-7899 Mannermaa, A. McCarthy, M.I. https://orcid.org/0000-0002-4393-0510 Meitinger, T. https://orcid.org/0000-0002-8838-8403 Menni, C. https://orcid.org/0000-0001-9790-0571 Michailidou, K. https://orcid.org/0000-0001-7065-1237 Millwood, I.Y. https://orcid.org/0000-0002-0807-0682 Milne, R.L. https://orcid.org/0000-0001-5764-7268 Montgomery, G.W. https://orcid.org/0000-0002-4140-8139 Nevanlinna, H. https://orcid.org/0000-0002-0916-2976 Nolte, I.M. https://orcid.org/0000-0001-5047-4077 Nyholt, D.R. https://orcid.org/0000-0001-7159-3040 Obi, N. O’Brien, K.M. Offit, K. Oldehinkel, A.J. https://orcid.org/0000-0003-3925-3913 Ostrowski, S.R. https://orcid.org/0000-0001-5288-3851 Palotie, A. https://orcid.org/0000-0002-2527-5874 Pedersen, O.B. https://orcid.org/0000-0003-2312-5976 Peters, A. Pianigiani, G. 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Winqvis, R. https://orcid.org/0000-0003-0932-9104 Pharoah, P.D.P. https://orcid.org/0000-0001-8494-732X Li, L. https://orcid.org/0000-0001-5873-7089 Easton, D.F. https://orcid.org/0000-0003-2444-3247 Njølstad, P.R. https://orcid.org/0000-0003-0304-6728 Sulem, P. https://orcid.org/0000-0001-7123-6123 Murabito, J.M. Murray, A. https://orcid.org/0000-0002-2351-2522 Manousaki, D. Juul, A. https://orcid.org/0000-0002-0534-4350 Erikstrup, C. https://orcid.org/0000-0001-6551-6647 Stefansson, K. https://orcid.org/0000-0003-1676-864X Horikoshi, M. https://orcid.org/0000-0002-7103-2267 Chen, Z. https://orcid.org/0000-0001-6423-105X Farooqi, I.S. Pitteloud, N. Johansson, S. https://orcid.org/0000-0002-2298-7008 Day, F.R. https://orcid.org/0000-0003-3789-7651 Perry, J.R.B. https://orcid.org/0000-0001-6483-3771 Ong, K.K. https://orcid.org/0000-0003-4689-7530
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Humans; Female; Menarche; Puberty; Gene Frequency; Animals; Multifactorial Inheritance; Mice; Genome-Wide Association Study; Adolescent; Puberty, Precocious; Polymorphism, Single Nucleotide; Receptors, G-Protein-Coupled; Puberty, Delayed; Child
Dates:	Published: 1 July 2024 Published (online): 1 July 2024 Accepted: 13 May 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	22 Jul 2024 10:55
Last Modified:	19 Aug 2024 10:00
Published Version:	http://dx.doi.org/10.1038/s41588-024-01798-4
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-024-01798-4
Related URLs:	PubMed URL Dataset Erratum/Corrigendum
Sustainable Development Goals:
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:215024