TY - JOUR
T1 - Understanding the genetic complexity of puberty timing across the allele frequency spectrum
AU - ABCTB Investigators
AU - The Lifelines Cohort Study
AU - The Danish Blood Donor Study
AU - The Biobank Japan Project
AU - The China Kadoorie Biobank Collaborative Group
AU - Kentistou, Katherine A.
AU - Kaisinger, Lena R.
AU - Stankovic, Stasa
AU - Vaudel, Marc
AU - Mendes de Oliveira, Edson
AU - Messina, Andrea
AU - Walters, Robin G.
AU - Liu, Xiaoxi
AU - Busch, Alexander S.
AU - Helgason, Hannes
AU - Thompson, Deborah J.
AU - Santoni, Federico
AU - Petricek, Konstantin M.
AU - Zouaghi, Yassine
AU - Huang-Doran, Isabel
AU - Gudbjartsson, Daniel F.
AU - Bratland, Eirik
AU - Lin, Kuang
AU - Gardner, Eugene J.
AU - Zhao, Yajie
AU - Jia, Raina Y.
AU - Terao, Chikashi
AU - Riggan, Marjorie J.
AU - Bolla, Manjeet K.
AU - Yazdanpanah, Mojgan
AU - Yazdanpanah, Nahid
AU - Bradfield, Jonathan P.
AU - Broer, Linda
AU - Campbell, Archie
AU - Chasman, Daniel I.
AU - Cousminer, Diana L.
AU - Franceschini, Nora
AU - Franke, Lude H.
AU - Girotto, Giorgia
AU - He, Chunyan
AU - Järvelin, Marjo Riitta
AU - Joshi, Peter K.
AU - Kamatani, Yoichiro
AU - Karlsson, Robert
AU - Luan, Jian’an
AU - Lunetta, Kathryn L.
AU - Mägi, Reedik
AU - Mangino, Massimo
AU - Medland, Sarah E.
AU - Meisinger, Christa
AU - Noordam, Raymond
AU - Nutile, Teresa
AU - Concas, Maria Pina
AU - Polašek, Ozren
AU - Daly, Mary B.
N1 - Publisher Copyright:
© The Author(s) 2024. corrected publication 2024.
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85199125224
U2 - 10.1038/s41588-024-01798-4
DO - 10.1038/s41588-024-01798-4
M3 - Article
C2 - 38951643
AN - SCOPUS:85199125224
SN - 1061-4036
VL - 56
SP - 1397
EP - 1411
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -