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

• Published in: Nature genetics Vol. 56; no. 7; pp. 1397 - 1411
• Main Authors: Kaisinger, Lena R, Stankovic, Stasa, Messina, Andrea, Busch, Alexander S, Santoni, Federico, Petricek, Konstantin M, Huang-Doran, Isabel, Gudbjartsson, Daniel F, Gardner, Eugene J, Bolla, Manjeet K, Campbell, Archie, Joshi, Peter K, Karlsson, Robert, Medland, Sarah E, Meisinger, Christa, Polašek, Ozren, Porcu, Eleonora, Smith, Albert V, Tanaka, Toshiko, van der Most, Peter J, Vitart, Veronique, Wang, Carol A, Willemsen, Gonneke, Ahearn, Thomas U, Andrulis, Irene L, Bogdanova, Natalia V, Buring, Julie E, Canzian, Federico, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Fasching, Peter A, Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, García-Closas, Montserrat, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hakonarson, Hakon, Hart, Roger J, Hooning, Maartje J, Hoppe, Reiner, Hu, Frank B, Huebner, Hanna, Jernström, Helena, Khusnutdinova, Elza K, Lacey, James V, Launer, Lenore J, Magnusson, Patrik K E, Mannermaa, Arto, McCarthy, Mark I, Meitinger, Thomas, Millwood, Iona Y, Milne, Roger L, Montgomery, Grant W, Nolte, Ilja M, Obi, Nadia, Offit, Kenneth, Ostrowski, Sisse R, Palotie, Aarno, Pedersen, Ole B, Saloustros, Emmanouil, Sandler, Dale P, Schmidt, Carsten O, Stampfer, Meir, Tamimi, Rulla M, Turman, Constance, Wolk, Alicja, Zheng, Wei, Alizadeh, Behrooz Z, Bandinelli, Stefania, Boerwinkle, Eric, Gieger, Christian, Hayward, Caroline, Nøhr, Ellen A, Snieder, Harold, Sovio, Ulla, Stöckl, Doris, Sudlow, Cathie, Timpson, Nic J, Toniolo, Daniela, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Widen, Elisabeth, Pharoah, Paul D P, Easton, Douglas F, Njølstad, Pål R, Manousaki, Despoina, Juul, Anders, Stefansson, Kari, Horikoshi, Momoko, Farooqi, I Sadaf, Pitteloud, Nelly, Johansson, Stefan
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2024; Nature Publishing Group US
• Subjects: Adolescent; adult; animal; animal experiment; Animals; Bardet Biedl syndrome; Basic Medicine; Biobanks; bioluminescence resonance energy transfer; blood donor; Body size; Child; chromatin immunoprecipitation; Consortia; controlled study; cyclic nucleotide; delayed puberty; DNA damage; DNA damage response; Female; Females; follitropin; Frequency spectrum; G protein coupled receptor; G protein-coupled receptors; Gene Frequency; gene linkage disequilibrium; Gene mapping; Gene sequencing; Genes; Genetic analysis; genetic risk score; genetics; Genome-Wide Association Study; Genomes; Genomics; gonadorelin; Gonadotropin-releasing hormone; Gonadotropins; happy puppet syndrome; histone demethylase; human; Humans; hypogonadotropic hypogonadism; Independent sample; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Menarche; Menarche - genetics; Menopause; Mice; mouse; Multifactorial Inheritance; Multifactorial Inheritance - genetics; nonhuman; Ovarian cancer; ovarian reserve; overlapping gene; Peptide mapping; Pituitary (anterior); Polygenic inheritance; Polymorphism, Single Nucleotide; precocious puberty; protein interaction; Proteins; Puberty; Puberty - genetics; Puberty, Delayed; Puberty, Delayed - genetics; Puberty, Precocious; Puberty, Precocious - genetics; Receptors, G-Protein-Coupled; Receptors, G-Protein-Coupled - genetics; RNA sequencing; signal transduction; single nucleotide polymorphism; somatomedin; Womens health; zinc finger protein; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-024-01798-4

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.