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

doi:10.2337/db20-0070

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

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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, …

Diabetes (New York, N.Y.), Vol.69(12), pp.2806-2818

01/12/2020

DOI: https://doi.org/10.2337/db20-0070

PMID: 32917775

Abstract

Adiposity - genetics

Gene Expression Regulation, Developmental

Genetic Variation

Genotype

Humans

Leptin - blood

Leptin - chemistry

Leptin - genetics

Leptin - metabolism

Models, Molecular

Protein Conformation

Racial Groups - genetics

Leptin influences food intake by informing the brain about the status of body fat stores. Rare 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 , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10 , = 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.

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Title: Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
Creators: Hanieh Yaghootkar - University of Exeter
Yiying Zhang - Columbia University
Cassandra N Spracklen - University of Massachusetts Amherst
Tugce Karaderi - Wellcome Centre for Human Genetics
Lam Opal Huang - Novo Nordisk Foundation
Jonathan Bradfield - Children's Hospital of Philadelphia
Claudia Schurmann - Icahn School of Medicine at Mount Sinai
Rebecca S Fine - Harvard University
Michael H Preuss - Icahn School of Medicine at Mount Sinai
Zoltan Kutalik - University of Lausanne
Laura B L Wittemans - Wellcome Centre for Human Genetics
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Sophia Metz - Novo Nordisk Foundation
Sara M Willems - University of Cambridge
Ruifang Li-Gao - Leiden University Medical Center
Niels Grarup - University of Copenhagen
Shuai Wang - Boston University
Sophie Molnos - German Center for Diabetes Research
América A Sandoval-Zárate - Institute for Molecular Medicine Finland
Mike A Nalls - National Institute on Aging
Leslie A Lange - University of Colorado Denver
Jeffrey Haesser - Fred Hutch Cancer Center
Xiuqing Guo - Harbor–UCLA Medical Center
Leo-Pekka Lyytikäinen - Tampere University
Mary F Feitosa - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO
Colleen M Sitlani - University of Washington
Cristina Venturini - King's College London
Anubha Mahajan - University of Oxford
Tim Kacprowski - Greifswald University Hospital
Carol A Wang - Boston University
Daniel I Chasman - Brigham and Women's Hospital
Najaf Amin - Erasmus MC
Linda Broer - Erasmus MC
Neil Robertson - University of Oxford
Kristin L Young - University of North Carolina at Chapel Hill
Matthew Allison - University of California, San Diego
Paul L Auer - University of Wisconsin–Milwaukee
Matthias Blüher - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
Judith B Borja - University of San Carlos
Jette Bork-Jensen - Novo Nordisk Foundation
Germán D Carrasquilla - Novo Nordisk Foundation
Paraskevi Christofidou - King's College London
Ayse Demirkan - Erasmus MC
Claudia A Doege - Columbia University
Melissa E Garcia - National Institute on Aging
Mariaelisa Graff - University of North Carolina at Chapel Hill
Kaiying Guo - Columbia University
Hakon Hakonarson - Children's Hospital of Philadelphia
Jaeyoung Hong - Boston University
Yii-Der Ida Chen - Harbor–UCLA Medical Center
Rebecca Jackson - The Ohio State University
Hermina Jakupović - Novo Nordisk Foundation
Pekka Jousilahti - Finnish Institute for Health and Welfare
Anne E Justice - Geisinger Medical Center
Mika Kähönen - Tampere University
Jorge R Kizer - University of California, San Francisco
Jennifer Kriebel - German Center for Diabetes Research
Charles A LeDuc - Columbia University
Jin Li - Stanford University
Lars Lind - Uppsala University
Jian'an Luan - University of Cambridge
David A Mackey - Lions Eye Institute
Massimo Mangino - Guy's and St Thomas' NHS Foundation Trust
Satu Männistö - Finnish Institute for Health and Welfare
Jayne F Martin Carli - Columbia University
Carolina Medina-Gomez - Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
Dennis O Mook-Kanamori - Leiden University Medical Center
Andrew P Morris - University of Liverpool
Renée de Mutsert - Leiden University Medical Center
Matthias Nauck - German Centre for Cardiovascular Research
Ivana Prokic - Erasmus MC
Craig E Pennell - Boston University
Arund D Pradhan - Brigham and Women's Hospital
Bruce M Psaty - University of Washington
Olli T Raitakari - Turku University Hospital
Robert A Scott - University of Cambridge
Tea Skaaby - Frederiksberg Hospital
Konstantin Strauch - Helmholtz Zentrum München
Kent D Taylor - Harbor–UCLA Medical Center
Alexander Teumer - German Centre for Cardiovascular Research
Andre G Uitterlinden - Erasmus MC
Ying Wu - University of North Carolina at Chapel Hill
Jie Yao - Harbor–UCLA Medical Center
Mark Walker - Newcastle University
Kari E North - University of North Carolina at Chapel Hill
Peter Kovacs - Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
M Arfan Ikram - Erasmus MC
Cornelia M van Duijn - Erasmus MC
Paul M Ridker - Brigham and Women's Hospital
Stephen Lye - Lunenfeld-Tanenbaum Research Institute
Georg Homuth - Greifswald University Hospital
Erik Ingelsson - Stanford University
Tim D Spector - King's College London
Barbara McKnight - University of Washington
Michael A Province - Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO
Terho Lehtimäki - Tampere University
Linda S Adair - University of North Carolina at Chapel Hill
Jerome I Rotter - Harbor–UCLA Medical Center
Alexander P Reiner - Fred Hutch Cancer Center
James G Wilson - University of Mississippi Medical Center
Tamara B Harris - National Institute on Aging
Samuli Ripatti - Institute for Molecular Medicine Finland
Harald Grallert - German Center for Diabetes Research
James B Meigs - Massachusetts General Hospital
Veikko Salomaa - Finnish Institute for Health and Welfare
Torben Hansen - University of Copenhagen
Ko Willems van Dijk - Leiden University Medical Center
Nicholas J Wareham - MRC Epidemiology Unit
Struan F A Grant - Children's Hospital of Philadelphia
Claudia Langenberg - University of Cambridge
Timothy M Frayling - University of Exeter
Cecilia M Lindgren - University of Oxford
Karen L Mohlke - University of North Carolina at Chapel Hill
Rudolph L Leibel - Columbia University
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Tuomas O Kilpeläinen - University of Copenhagen
Publication Details: Diabetes (New York, N.Y.), Vol.69(12), pp.2806-2818
Date published: 01/12/2020
Grant note: U01 HL130114 / NHLBI NIH HHS R01 HL149683 / NHLBI NIH HHS MC_UU_12015/1 / Medical Research Council P30 DK020541 / NIDDK NIH HHS R01 DK093757 / NIDDK NIH HHS F31 HG009850 / NHGRI NIH HHS MR/T002239/1 / Medical Research Council P30 DK056341 / NIDDK NIH HHS MC_UU_00006/1 / Medical Research Council R01 HL105756 / NHLBI NIH HHS
Identifiers: 99828461302346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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