Hanieh Yaghootkar, Yiying Zhang, Cassandra N. Spracklen, Tugce Karaderi, Lam Opal Huang, Jonathan Bradfield, Claudia Schurmann, Rebecca S. Fine, Michael H. Preuss, Zoltan Kutalik, Laura B.L. Wittemans, Yingchang Lu, Sophia Metz, Sara M. Willems, Ruifang Li-Gao, Niels Grarup, Shuai Wang, Sophie Molnos, América A. Sandoval-Zárate, Mike A. Nalls, Leslie A. Lange, Jeffrey Haesser, Xiuqing Guo, Leo-Pekka Lyytikäinen, Mary F. Feitosa, Colleen M. Sitlani, Cristina Venturini, Anubha Mahajan, Tim Kacprowski, Carol A. Wang, Daniel I. Chasman, Najaf Amin, Linda Broer, Neil Robertson, Kristin L. Young, Matthew Allison, Paul L. Auer, Matthias Blüher, Judith B. Borja, Jette Bork-Jensen, Germán D. Carrasquilla, Paraskevi Christofidou, Ayse Demirkan, Claudia A. Doege, Melissa E. Garcia, Mariaelisa Graff, Kaiying Guo, Hakon Hakonarson, Jaeyoung Hong, Yii-Der Ida Chen, Rebecca Jackson, Hermina Jakupovic, Pekka Jousilahti, Anne E. Justice, Mika Kähönen, Jorge R. Kizer, Jennifer Kriebel, Charles A. Leduc, Jin Li, Lars Lind, Jian’An Luan, David A. Mackey, Massimo Mangino, Satu Männistö, Jayne F. Martin Carli, Carolina Medina-Gomez, Dennis O. Mook-Kanamori, Andrew P. Morris, Renée de Mutsert, Matthias Nauck, Ivana Prokic, Craig E. Pennell, Arund D. Pradhan, Bruce M. Psaty, Olli T. Raitakari, Robert A. Scott, Tea Skaaby, Konstantin Strauch, Kent D. Taylor, Alexander Teumer, Andre G. Uitterlinden, Ying Wu, Jie Yao, Mark Walker, Kari E. North, Peter Kovacs, M. Arfan Ikram, Cornelia M. van Duijn, Paul M. Ridker, Stephen Lye, Georg Homuth, Erik Ingelsson, Tim D. Spector, Barbara McKnight, Michael A. Province, Terho Lehtimäki, Linda S. Adair, Jerome I. Rotter, Alexander P. Reiner, James G. Wilson, Tamara B. Harris, Samuli Ripatti, Harald Grallert, James B. Meigs, Veikko Salomaa, Torben Hansen, Ko Willems van Dijk, Nicholas J. Wareham, Struan F.A. Grant, Claudia Langenberg, Timothy M. Frayling, Cecilia M. Lindgren, Karen L. Mohlke, Rudolph L. Leibel, Ruth J.F. Loos, Tuomas O. Kilpeläinen
Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity. © 2020 by the American Diabetes Association.
Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom; Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom; Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY, United States; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, MA, United States; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; DTU Health Technology, Technical University of Denmark, Lyngby, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Center for Applied Genomics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States; Quantinuum Research LLC, San Diego, CA, United States; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Genetics, Harvard Medical School, Boston, MA, United States; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States; Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom; Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, United States; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States; German Center for Diabetes Research, München-Neuherberg, Germany; Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg, Germany; Institute for Molecular Medicine Finland, Helsinki, Finland; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States; Data Tecnica International, Glen Echo, MD, United States; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, CO, United States; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States; Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifs-wald, Greifswald, Germany; Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, United States; Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, United States; Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Office of Population Studies Foundation, Inc., Cebu City, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines; Department of Pathology and Cell Biology, Columbia University, New York, NY, United States; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, United States; Carolina Center for Genome Sciences, Chapel Hill, NC, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH, United States; Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; Center for Biomedical and Translational Informatics, Geisinger, Danville, PA, United States; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Cardiology Section, San Francisco Veterans Affairs Health Care System, University of California San Francisco, San Francisco, CA, United States; Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, CA, United States; Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Centre for Ophthalmology and Visual Science, Lions Eye Institute, The University of Western Australia, Perth, West Australia, Australia; NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, United Kingdom; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, United Kingdom; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, United States; Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States; Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, Turku University Hospital, Turku, Finland; Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Insitute of Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, Ludwig Maximilian University Munich, München, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne, United Kingdom; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Stanford Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, United States; Stanford Diabetes Research Center, Stanford University, Stanford, CA, United States; Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Biostatistics, University of Washington, Seattle, WA, United States; Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States; Public Health, University of Helsinki, Helsinki, Finland; Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States; Department of Medicine, Harvard Medical School, Boston, MA, United States; Population and Medical Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States; Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands; Center for Spatial and Functional Genomics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States; Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States; Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
