Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
Kentistou KA., Kaisinger LR., Stankovic S., Vaudel M., de Oliveira EM., Messina A., Walters RG., Liu X., Busch AS., Helgason H., Thompson DJ., Santon F., Petricek KM., Zouaghi Y., Huang-Doran I., Gudbjartsson DF., Bratland E., Lin K., Gardner EJ., Zhao Y., Jia R., Terao C., Riggan M., Bolla MK., Yazdanpanah M., Yazdanpanah N., Bradfield JP., Broer L., Campbell A., Chasman DI., Cousminer DL., Franceschini N., Franke LH., Girotto G., He C., Järvelin M-R., Joshi PK., Kamatani Y., Karlsson R., Luan J., Lunetta KL., Mägi R., Mangino M., Medland SE., Meisinger C., Noordam R., Nutile T., Concas MP., Polašek O., Porcu E., Ring SM., Sala C., Smith AV., Tanaka T., van der Most PJ., Vitart V., Wang CA., Willemsen G., Zygmunt M., Ahearn TU., Andrulis IL., Anton-Culver H., Antoniou AC., Auer PL., Barnes CL., Beckmann MW., Berrington A., Bogdanova NV., Bojesen SE., Brenner H., Buring JE., Canzian F., Chang-Claude J., Couch FJ., Cox A., Crisponi L., Czene K., Daly MB., Demerath EW., Dennis J., Devilee P., Vivo ID., Dörk T., Dunning AM., Dwek M., Eriksson JG., Fasching PA., Fernandez-Rhodes L., Ferreli L., Fletcher O., Gago-Dominguez M., García-Closas M., García-Sáenz JA., González-Neira A., Grallert H., Guénel P., Haiman CA., Hall P., Hamann U., Hakonarson H., Hart RJ., Hickey M., Hooning MJ., Hoppe R., Hopper JL., Hottenga J-J., Hu FB., Hübner H., Hunter DJ., ABCTB Investigators None., Jernström H., John EM., Karasik D., Khusnutdinova EK., Kristensen VN., Lacey JV., Lambrechts D., Launer LJ., Lind PA., Lindblom A., Magnusson PK., Mannermaa A., McCarthy MI., Meitinger T., Menni C., Michailidou K., Millwood IY., Milne RL., Montgomery GW., Nevanlinna H., Nolte IM., Nyholt DR., Obi N., O'Brien KM., Offit K., Oldehinkel AJ., Ostrowski SR., Palotie A., Pedersen OB., Peters A., Pianigiani G., Plaseska-Karanfilska D., Pouta A., Pozarickij A., Radice P., Rennert G., Rosendaal FR., Ruggiero D., Saloustros E., Sandler DP., Schipf S., Schmidt CO., Schmidt MK., Small K., Spedicati B., Stampfer M., Stone J., Tamimi RM., Teras LR., Tikkanen E., Turman C., Vachon CM., Wang Q., Winqvist R., Wolk A., Zemel BS., Zheng W., van Dijk KW., Alizadeh BZ., Bandinelli S., Boerwinkle E., Boomsma DI., Ciullo M., Chenevix-Trench G., Cucca F., Esko T., Gieger C., Grant SF., Gudnason V., Hayward C., Kolčić I., Kraft P., Lawlor DA., Martin NG., Nøhr EA., Pedersen NL., Pennell CE., Ridker PM., Robino A., Snieder H., Sovio U., Spector TD., Stöckl D., Sudlow C., Timpson NJ., Toniolo D., Uitterlinden A., Ulivi S., Völzke H., Wareham NJ., Widen E., Wilson JF., Lifelines Cohort Study None., Danish Blood Donor study None., Ovarian Cancer Association Consortium None., Breast Cancer Association Consortium None., Biobank Japan Project None., China Kadoorie Biobank Collaborative Group None., Pharoah PD., Li L., Easton DF., Njølstad P., Sulem P., Murabito JM., Murray A., Manousaki D., Juul A., Erikstrup C., Stefansson K., Horikoshi M., Chen Z., Farooqi IS., Pitteloud N., Johansson S., Day FR., Perry JR., Ong KK.
Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.