Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K. h.yaghootkar@exeter.ac.uk tuomas.kilpelainen@sund.ku.dk. 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, U.K. Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC. Department of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, MA. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. 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. Quantinuum Research LLC, San Diego, CA. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Department of Genetics, Harvard Medical School, Boston, MA. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA. Broad Institute of MIT and Harvard, Cambridge, MA. Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K. 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, U.K. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, and Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. Department of Biostatistics, Boston University School of Public Health, Boston, MA. 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. Data Tecnica International, Glen Echo, MD. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, CO. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA. 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. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA. Department of Twin Research and Genetic Epidemiology, Kings College London, London, U.K. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA. Harvard Medical School, Boston, MA. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC. Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA. Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI. 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. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD. Carolina Center for Genome Sciences, Chapel Hill, NC. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH. Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland. Center for Biomedical and Translational Informatics, Geisinger, Danville, PA. 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. Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, CA. 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, U.K. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. Department of Biostatistics, University of Liverpool, Liverpool, U.K. Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, U.K. 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. Kaiser Permanente Washington Health Research Institute, Seattle, WA. Centre for Population Health Research, University of Turku and 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. Chair of Genetic Epidemiology, 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, U.K. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Stanford Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA. Stanford Diabetes Research Center, Stanford University, Stanford, CA. Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Department of Biostatistics, University of Washington, Seattle, WA. Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD. Public Health, University of Helsinki, Helsinki, Finland. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. Program in Population and Medical Genetics, Broad Institute of MIT and Harvard, Cambridge, MA. Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands. Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. Center for Spatial and Functional Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA. Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA. Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark h.yaghootkar@exeter.ac.uk tuomas.kilpelainen@sund.ku.dk. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY.

Diabetes. 2020;(12):2806-2818

Abstract

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 administering 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 concentrations. 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.