Understanding the genetic complexity of puberty timing across the allele frequency spectrum
(2024) In Nature Genetics 56(7). p.1397-1411- 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,... (More)
- 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. © The Author(s) 2024. corrected publication 2024. (Less)
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https://lup.lub.lu.se/record/75bc120b-b5f0-4c79-99c6-3d8ca9ac7cec
- author
- Kentistou, K.A. ; Jernström, H. LU and Ong, Ken K.
- author collaboration
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Adolescent, Animals, Child, Female, Gene Frequency, Genome-Wide Association Study, Humans, Menarche, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Puberty, Puberty, Delayed, Puberty, Precocious, Receptors, G-Protein-Coupled, cyclic nucleotide, follitropin, G protein coupled receptor, gonadorelin, histone demethylase, somatomedin, zinc finger protein, adult, animal experiment, Article, Bardet Biedl syndrome, bioluminescence resonance energy transfer, blood donor, chromatin immunoprecipitation, controlled study, DNA damage response, female, gene frequency, gene linkage disequilibrium, gene mapping, genetic risk score, happy puppet syndrome, human, hypogonadotropic hypogonadism, menopause, mouse, nonhuman, ovarian reserve, overlapping gene, precocious puberty, protein interaction, puberty, RNA sequencing, signal transduction, adolescent, animal, child, delayed puberty, genetics, genome-wide association study, menarche, multifactorial inheritance, single nucleotide polymorphism
- in
- Nature Genetics
- volume
- 56
- issue
- 7
- pages
- 15 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85199125224
- ISSN
- 1061-4036
- DOI
- 10.1038/s41588-024-01798-4
- language
- English
- LU publication?
- yes
- id
- 75bc120b-b5f0-4c79-99c6-3d8ca9ac7cec
- date added to LUP
- 2024-09-13 12:48:17
- date last changed
- 2024-09-13 12:49:02
@article{75bc120b-b5f0-4c79-99c6-3d8ca9ac7cec,
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. © The Author(s) 2024. corrected publication 2024.}},
author = {{Kentistou, K.A. and Jernström, H. and Ong, Ken K.}},
issn = {{1061-4036}},
keywords = {{Adolescent; Animals; Child; Female; Gene Frequency; Genome-Wide Association Study; Humans; Menarche; Mice; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Puberty; Puberty, Delayed; Puberty, Precocious; Receptors, G-Protein-Coupled; cyclic nucleotide; follitropin; G protein coupled receptor; gonadorelin; histone demethylase; somatomedin; zinc finger protein; adult; animal experiment; Article; Bardet Biedl syndrome; bioluminescence resonance energy transfer; blood donor; chromatin immunoprecipitation; controlled study; DNA damage response; female; gene frequency; gene linkage disequilibrium; gene mapping; genetic risk score; happy puppet syndrome; human; hypogonadotropic hypogonadism; menopause; mouse; nonhuman; ovarian reserve; overlapping gene; precocious puberty; protein interaction; puberty; RNA sequencing; signal transduction; adolescent; animal; child; delayed puberty; genetics; genome-wide association study; menarche; multifactorial inheritance; single nucleotide polymorphism}},
language = {{eng}},
number = {{7}},
pages = {{1397--1411}},
publisher = {{Nature Publishing Group}},
series = {{Nature Genetics}},
title = {{Understanding the genetic complexity of puberty timing across the allele frequency spectrum}},
url = {{http://dx.doi.org/10.1038/s41588-024-01798-4}},
doi = {{10.1038/s41588-024-01798-4}},
volume = {{56}},
year = {{2024}},
}