Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
01 Jul 2024
01 Jul 2024
Historique:
received:
12
06
2023
accepted:
13
05
2024
medline:
2
7
2024
pubmed:
2
7
2024
entrez:
1
7
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38951643
doi: 10.1038/s41588-024-01798-4
pii: 10.1038/s41588-024-01798-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_00006/2
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_00006/2
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_00006/2
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_00006/2
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_00006/2
Investigateurs
Esther M John
(EM)
Per Hall
(P)
Robert Winqvis
(R)
Informations de copyright
© 2024. The Author(s).
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