Genetics/Genomes/Proteomics/Metabolomics

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

  1. Hanieh Yaghootkar1,2,3⇑,
  2. Yiying Zhang4,
  3. Cassandra N. Spracklen5,6,
  4. Tugce Karaderi7,8,9,10,
  5. Lam Opal Huang11,
  6. Jonathan Bradfield12,13,
  7. Claudia Schurmann14,
  8. Rebecca S. Fine15,16,17,
  9. Michael H. Preuss14,
  10. Zoltan Kutalik1,18,19,
  11. Laura B.L. Wittemans7,20,
  12. Yingchang Lu14,21,
  13. Sophia Metz11,
  14. Sara M. Willems20,
  15. Ruifang Li-Gao22,
  16. Niels Grarup11,
  17. Shuai Wang23,
  18. Sophie Molnos24,25,
  19. América A. Sandoval-Zárate26,
  20. Mike A. Nalls27,28,
  21. Leslie A. Lange29,
  22. Jeffrey Haesser30,
  23. Xiuqing Guo31,
  24. Leo-Pekka Lyytikäinen32,33,
  25. Mary F. Feitosa34,
  26. Colleen M. Sitlani35,
  27. Cristina Venturini36,
  28. Anubha Mahajan7,37,
  29. Tim Kacprowski38,39,
  30. Carol A. Wang23,
  31. Daniel I. Chasman40,41,
  32. Najaf Amin42,
  33. Linda Broer43,
  34. Neil Robertson7,37,
  35. Kristin L. Young44,
  36. Matthew Allison45,
  37. Paul L. Auer46,
  38. Matthias Blüher47,
  39. Judith B. Borja48,49,
  40. Jette Bork-Jensen11,
  41. Germán D. Carrasquilla11,
  42. Paraskevi Christofidou36,
  43. Ayse Demirkan42,
  44. Claudia A. Doege50,
  45. Melissa E. Garcia51,
  46. Mariaelisa Graff44,52,
  47. Kaiying Guo4,
  48. Hakon Hakonarson12,53,
  49. Jaeyoung Hong23,
  50. Yii-Der Ida Chen31,
  51. Rebecca Jackson54,
  52. Hermina Jakupović11,
  53. Pekka Jousilahti55,
  54. Anne E. Justice56,
  55. Mika Kähönen57,58,
  56. Jorge R. Kizer59,60,
  57. Jennifer Kriebel24,25,
  58. Charles A. LeDuc4,
  59. Jin Li61,
  60. Lars Lind62,
  61. Jian’an Luan20,
  62. David A. Mackey63,
  63. Massimo Mangino36,64,
  64. Satu Männistö55,
  65. Jayne F. Martin Carli4,
  66. Carolina Medina-Gomez42,43,
  67. Dennis O. Mook-Kanamori22,65,
  68. Andrew P. Morris7,66,67,
  69. Renée de Mutsert22,
  70. Matthias Nauck39,68,
  71. Ivana Prokic42,
  72. Craig E. Pennell23,
  73. Arund D. Pradhan40,41,
  74. Bruce M. Psaty69,70,
  75. Olli T. Raitakari71,72,73,
  76. Robert A. Scott20,
  77. Tea Skaaby74,
  78. Konstantin Strauch75,76,
  79. Kent D. Taylor31,
  80. Alexander Teumer39,77,
  81. Andre G. Uitterlinden42,43,
  82. Ying Wu5,
  83. Jie Yao31,
  84. Mark Walker78,
  85. Kari E. North44,
  86. Peter Kovacs47,
  87. M. Arfan Ikram42,43,
  88. Cornelia M. van Duijn42,
  89. Paul M. Ridker40,41,
  90. Stephen Lye79,
  91. Georg Homuth38,
  92. Erik Ingelsson61,80,81,82,
  93. Tim D. Spector36,
  94. Barbara McKnight83,
  95. Michael A. Province34,
  96. Terho Lehtimäki32,33,
  97. Linda S. Adair84,
  98. Jerome I. Rotter31,
  99. Alexander P. Reiner30,
  100. James G. Wilson85,
  101. Tamara B. Harris86,
  102. Samuli Ripatti17,26,87,
  103. Harald Grallert24,25,
  104. James B. Meigs88,89,90,
  105. Veikko Salomaa55,
  106. Torben Hansen11,
  107. Ko Willems van Dijk91,92,93,
  108. Nicholas J. Wareham20,
  109. Struan F.A. Grant12,53,94,95,96,
  110. Claudia Langenberg20,
  111. Timothy M. Frayling1,
  112. Cecilia M. Lindgren7,17,97,
  113. Karen L. Mohlke5,
  114. Rudolph L. Leibel4,
  115. Ruth J.F. Loos14,98 and
  116. Tuomas O. Kilpeläinen11,99⇑
  1. 1Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K.
  2. 2Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
  3. 3Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K.
  4. 4Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY
  5. 5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
  6. 6Department of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, MA
  7. 7Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  8. 8Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus
  9. 9Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  10. 10DTU Health Technology, Technical University of Denmark, Lyngby, Denmark
  11. 11Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  12. 12Center for Applied Genomics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA
  13. 13Quantinuum Research LLC, San Diego, CA
  14. 14The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
  15. 15Department of Genetics, Harvard Medical School, Boston, MA
  16. 16Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA
  17. 17Broad Institute of MIT and Harvard, Cambridge, MA
  18. 18Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland
  19. 19Swiss Institute of Bioinformatics, Lausanne, Switzerland
  20. 20MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
  21. 21Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, and Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN
  22. 22Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
  23. 23Department of Biostatistics, Boston University School of Public Health, Boston, MA
  24. 24German Center for Diabetes Research, München-Neuherberg, Germany
  25. 25Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, München-Neuherberg, Germany
  26. 26Institute for Molecular Medicine Finland, Helsinki, Finland
  27. 27Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD
  28. 28Data Tecnica International, Glen Echo, MD
  29. 29Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Denver, CO
  30. 30Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
  31. 31The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA
  32. 32Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
  33. 33Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  34. 34Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO
  35. 35Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
  36. 36Department of Twin Research and Genetic Epidemiology, Kings College London, London, U.K.
  37. 37Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
  38. 38Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
  39. 39DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
  40. 40Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA
  41. 41Harvard Medical School, Boston, MA
  42. 42Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
  43. 43Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
  44. 44Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
  45. 45Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA
  46. 46Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI
  47. 47Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
  48. 48Office of Population Studies Foundation, Inc., Cebu City, Philippines
  49. 49Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines
  50. 50Department of Pathology and Cell Biology, Columbia University, New York, NY
  51. 51Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD
  52. 52Carolina Center for Genome Sciences, Chapel Hill, NC
  53. 53Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  54. 54Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH
  55. 55Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland
  56. 56Center for Biomedical and Translational Informatics, Geisinger, Danville, PA
  57. 57Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
  58. 58Department of Clinical Physiology, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  59. 59Cardiology Section, San Francisco Veterans Affairs Health Care System, University of California San Francisco, San Francisco, CA
  60. 60Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA
  61. 61Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, CA
  62. 62Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  63. 63Centre for Ophthalmology and Visual Science, Lions Eye Institute, The University of Western Australia, Perth, West Australia, Australia
  64. 64NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, U.K.
  65. 65Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
  66. 66Department of Biostatistics, University of Liverpool, Liverpool, U.K.
  67. 67Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, U.K.
  68. 68Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
  69. 69Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA
  70. 70Kaiser Permanente Washington Health Research Institute, Seattle, WA
  71. 71Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
  72. 72Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  73. 73Research Centre of Applied and Preventive Cardiovascular Medicine, Turku University Hospital, Turku, Finland
  74. 74Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
  75. 75Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
  76. 76Chair of Genetic Epidemiology, Insitute of Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, Ludwig Maximilian University Munich, München, Germany
  77. 77Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  78. 78Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne, U.K.
  79. 79Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  80. 80Stanford Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA
  81. 81Stanford Diabetes Research Center, Stanford University, Stanford, CA
  82. 82Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  83. 83Department of Biostatistics, University of Washington, Seattle, WA
  84. 84Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
  85. 85Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS
  86. 86Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD
  87. 87Public Health, University of Helsinki, Helsinki, Finland
  88. 88Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA
  89. 89Department of Medicine, Harvard Medical School, Boston, MA
  90. 90Program in Population and Medical Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
  91. 91Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
  92. 92Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands
  93. 93Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  94. 94Center for Spatial and Functional Genomics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA
  95. 95Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
  96. 96Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  97. 97Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
  98. 98The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
  99. 99Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY
  1. Corresponding authors: Hanieh Yaghootkar, h.yaghootkar{at}exeter.ac.uk, and Tuomas O. Kilpeläinen, tuomas.kilpelainen{at}sund.ku.dk

  1. H.Y., Y.Z., R.J.F.L., and T.O.K. contributed equally to this study.

Diabetes 2020 Dec; 69(12): 2806-2818. https://doi.org/10.2337/db20-0070

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.

Footnotes

  • L.O.H. is currently affiliated with Steno Diabetes Center Copenhagen, Gentofte, Denmark. R.S.F. is currently affiliated with Vertex Pharmaceuticals Incorporated, Boston, MA. M.E.G. is currently affiliated with the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD.

  • This work was conducted prior to M.E.G.’s current affiliation with the NHLBI, and, as such, the views expressed in this article do not represent the views of the NHLBI, National Institutes of Health, or other government entity.

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12933737.

  • Received January 23, 2020.
  • Accepted September 9, 2020.
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
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 Jakupović, 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
Diabetes Dec 2020, 69 (12) 2806-2818; DOI: 10.2337/db20-0070
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