Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
About this Publication
Title
Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
Pubmed ID
37503126
(View this publication on the PubMed website)
Digital Object Identifier
Publication
medRxiv. 2023 Jun 20
Authors
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, ...show more 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 MR, 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 I, 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 JJ, Hu FB, Hübner H, Hunter DJ, ABCTB Investigators, 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, Danish Blood Donor study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, 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
Affiliations
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, NO-5020, Bergen, Norway.
- University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
- Division of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland.
- Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
- Department of General Pediatrics, University of Münster, Münster, Germany.
- deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany.
- Department of Gynecology, Duke University Medical Center, Durham, North Carolina, USA.
- Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada.
- Quantinuum Research, Wayne, PA, USA.
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK.
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
- Institute for Maternal and Child Health - IRCCS ''Burlo Garofolo", Trieste, Italy.
- Department of Epidemiology and Biostatistics, Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
- Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK.
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.
- Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Boston University School of Public Health, Department of Biostatistics. Boston, Massachusetts 02118, USA.
- Institute of Genomics, University of Tartu, Tartu, Estonia.
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital of Augsburg, Augsburg, Germany.
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, Naples, Italy.
- University of Split School of Medicine, Split, Croatia.
- Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Sardinia 09042, Italy.
- MRC Integrative Epidemiology Unit at the University of Bristol, UK.
- Division of Genetics and Cell Biology, San Raffele Hospital, Milano, Italy.
- Icelandic Heart Association, 201 Kopavogur, Iceland.
- National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands.
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
- School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales 2308, Australia.
- Dept of Biological Psychology, Vrije Universiteit, Amsterdam; Amsterdam Public Health (APH) research institute, The Netherlands.
- Clinic of Gynaecology and Obstetrics, University Medicine Greifswald, Germany.
- Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, Department of Health and Human Services Bethesda, MD, USA.
- Fred A. Litwin Center for Cancer Genetics Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital Toronto, Ontario, Canada.
- Department of Medicine, Genetic Epidemiology Research Institute University of California Irvine Irvine, CA, USA.
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center Medical College of Wisconsin Milwaukee, WI, USA.
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
- Division of Genetics and Epidemiology The Institute of Cancer Research, London, UK.
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
- Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.
- Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Genomic Epidemiology Group German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN, USA.
- Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
- Department of Clinical Genetics Fox Chase Cancer Center Philadelphia, PA, USA.
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, USA.
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
- School of Life Sciences, University of Westminster, London, UK.
- Department of General Practice and Primary Healthcare, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
- Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA.
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
- Genomic Medicine Group, International Cancer Genetics and Epidemiology Group Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS Santiago de Compostela, Spain.
- Medical Oncology Department, Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
- Team "Exposome and Heredity", CESP, Gustave Roussy INSERM, University Paris-Saclay, UVSQ Villejuif, France.
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Division of Obstetrics and Gynaecology, University of Western Australia, Western Australia, Australia.
- Department of Obstetrics and Gynaecology at the University of Melbourne and The Royal Women's Hospital, Victoria, Australia.
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne Melbourne, Victoria, Australia.
- Department of Nutrition, Harvard T.H. Chan School of Public Health School of Public Health, Boston, Massachusetts 02115, USA.
- Oncology, Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.
- Department of Epidemiology and Population Health, Stanford University School of Medicine Stanford, CA, USA.
- Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts, USA.
- Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
- Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
- Department of Computational and Quantitative Medicine, City of Hope Duarte, CA, USA.
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, 20892, USA.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
- School of Biomedical Sciences, Faculty of Health, Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Queensland, Australia.
- Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Epidemiology Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, NC, USA.
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York, NY, USA.
- Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, University of Groningen, The Netherlands.
- Department of Clinical Immunology, Rigshospitalet - University of Copenhagen, Copenhagen, Denmark.
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
- Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
- Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov" MASA Skopje Republic of North Macedonia.
- National Institute for Health and Welfare, Finland.
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research Fondazione IRCCS, Istituto Nazionale dei Tumori (INT), Milan, Italy.
- Clalit National Cancer Control Center, Carmel Medical Center and Technion, Faculty of Medicine, Haifa, Israel.
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
- Department of Oncology, University Hospital of Larissa, Larissa, Greece.
- Institute for Community Medicine, University Medicine Greifswald, Germany.
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
- Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia Perth, Western Australia, Australia.
- Department of Population Health Sciences Weill Cornell Medicine New York, NY, USA.
- Department of Population Science American Cancer Society Atlanta, GA, USA.
- Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
- Department of Quantitative Health Sciences, Division of Epidemiology Mayo Clinic Rochester, MN, USA.
- Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center Vanderbilt University School of Medicine Nashville, TN, USA.
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
- Geriatric Unit, Local Health Toscana Centro, Florence, Italy.
- Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
- Institute of Clinical Research, University of Southern Denmark, Department of Obstetrics & Gynecology, Odense University Hospital, Denmark.
- Gesundheitsamt Fürstenfeldbruck, Regierung von Oberbayern, Fürstenfeldbruck, Germany.
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
- NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
- Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Abstract
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.
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