Understanding the genetic complexity of puberty timing across the allele frequency spectrum
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Nature Research
https://doi.org/10.1038/s41588-024-01798-4
https://doi.org/10.1038/s41588-024-01798-4
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Acknowledgements: This research was supported by the UK Medical Research Council (MRC; Unit program MC_UU_00006/2) and has been conducted using the UK Biobank Resource under application 9905. Other study-specific acknowledgements can be found in the Supplementary Information.
Pubertal timing varies considerably and associates with later health outcomes. We performed multi-ancestry genetic analyses in ~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 risk of delayed and precocious puberty, respectively. We identified several genes harbouring 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 GnRH neuron RNAseq implicated 665 genes, including an uncharacterized G-protein coupled receptor, GPR83, which amplified 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.
This research was supported by the UK Medical Research Council (MRC; Unit programme MC_UU_00006/2) and has been conducted using the UK Biobank Resource under Application Number 9905. Other study specific acknowledgements can be found in the supplementary note
Pubertal timing varies considerably and associates with later health outcomes. We performed multi-ancestry genetic analyses in ~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 risk of delayed and precocious puberty, respectively. We identified several genes harbouring 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 GnRH neuron RNAseq implicated 665 genes, including an uncharacterized G-protein coupled receptor, GPR83, which amplified 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.
This research was supported by the UK Medical Research Council (MRC; Unit programme MC_UU_00006/2) and has been conducted using the UK Biobank Resource under Application Number 9905. Other study specific acknowledgements can be found in the supplementary note