Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Valérie Turcot(Montreal Heart Institute), Yingchang Lu(Vanderbilt University), Heather M. Highland(University of North Carolina at Chapel Hill), Claudia Schurmann(Icahn School of Medicine at Mount Sinai), Anne E. Justice(University of North Carolina at Chapel Hill), Rebecca S. Fine(Broad Institute), Jonathan P. Bradfield(Children's Hospital of Philadelphia), Tõnu Esko(Broad Institute), Ayush Giri(Vanderbilt University), Mariaelisa Graff(University of North Carolina at Chapel Hill), Xiuqing Guo(The Lundquist Institute), Audrey E. Hendricks(Wellcome Sanger Institute), Tugce Karaderi(Centre for Human Genetics), Adelheid Lempradl(Max Planck Institute of Immunobiology and Epigenetics), Adam E. Locke(James S. McDonnell Foundation), Anubha Mahajan(Centre for Human Genetics), Eirini Marouli(Queen Mary University of London), Suthesh Sivapalaratnam(University of Cambridge), Kristin L. Young(University of North Carolina at Chapel Hill), Tamuno Alfred(Icahn School of Medicine at Mount Sinai), Mary F. Feitosa, Nicholas G. D. Masca(University of Leicester), Alisa K. Manning(Broad Institute), Carolina Medina‐Gómez(Erasmus MC), Poorva Mudgal(Wake Forest University), Maggie C. Y. Ng(Wake Forest University), Alex P. Reiner(University of Washington), Sailaja Vedantam(Broad Institute), Sara M. Willems(University of Cambridge), Thomas W. Winkler(University of Regensburg), Gonçalo R. Abecasis(University of Michigan), Katja K.H. Aben(Radboud University Nijmegen), Dewan S Alam(York University), Sameer Alharthi(Queen Mary University of London), Matthew Allison(University of California San Diego), Philippe Amouyel(Inserm), Folkert W. Asselbergs(University Medical Center Utrecht), Paul L. Auer(University of Wisconsin–Milwaukee), Beverley Balkau(Inserm), Lia E. Bang(Copenhagen University Hospital), Inês Barroso(University of Cambridge), Lisa Bastarache(Vanderbilt University), Marianne Benn(University of Copenhagen), Sven Bergmann(SIB Swiss Institute of Bioinformatics), Lawrence F. Bielak(University of Michigan), Matthias Blüher(IFB Adiposity Diseases), Michael Boehnke(University of Michigan), Heiner Boeing(German Institute of Human Nutrition), Eric Boerwinkle(Baylor College of Medicine), Carsten A. Böger(University Hospital Regensburg), Jette Bork‐Jensen(University of Copenhagen), Michiel L. Bots(University Medical Center Utrecht), Erwin P. Böttinger(Icahn School of Medicine at Mount Sinai), Donald W. Bowden(Wake Forest University), Ivan Brandslund(University of Southern Denmark), Gerome Breen(King's College London), Murray H. Brilliant(Marshfield Clinic), Linda Broer(Erasmus MC), Marco Brumat(University of Trieste), Amber Burt(University of Washington), Adam S. Butterworth(University of Cambridge), Peter T. Campbell(American Cancer Society), Stefania Cappellani(IRCCS Materno Infantile Burlo Garofolo), David J. Carey(Geisinger Health System), Eulalia Catamo(IRCCS Materno Infantile Burlo Garofolo), Mark J. Caulfield(Queen Mary University of London), John C. Chambers(Imperial College Healthcare NHS Trust), Daniel I. Chasman(Broad Institute), Yii‐Der Ida Chen(The Lundquist Institute), Rajiv Chowdhury(University of Cambridge), Cramer Christensen(Lillebaelt Hospital), Audrey Y. Chu(Merck & Co., Inc., Rahway, NJ, USA (United States)), Massimiliano Cocca(University of Trieste), Francis S. Collins(National Institutes of Health), James P. Cook(University of Liverpool), Janie Corley(University of Edinburgh), Jordi Corominas Galbany(Radboud University Nijmegen), Amanda J. Cox(Griffith University), David S. Crosslin(University of Washington Medical Center), Gabriel Cuéllar-Partida(The University of Queensland), Angela D’Eustacchio(IRCCS Materno Infantile Burlo Garofolo), John Danesh(University of Cambridge), Gail Davies(University of Liverpool), Paul I. W. de Bakker(Utrecht University), Mark de Groot(Utrecht University), Renée de Mutsert(Leiden University Medical Center), Ian J. Deary(University of Liverpool), George Dedoussis(Harokopio University of Athens), Ellen W. Demerath(University of Minnesota), Martin den Heijer(Amsterdam UMC Location Vrije Universiteit Amsterdam), Anneke I. den Hollander(Radboud University Nijmegen), Hester M. den Ruijter(University Medical Center Utrecht), Joe Dennis(University of Cambridge), Joshua C. Denny(Vanderbilt University), Emanuele Di Angelantonio(University of Cambridge), Fotios Drenos(University of Bristol), Mengmeng Du(Memorial Sloan Kettering Cancer Center), Marie‐Pierre Dubé(Montreal Heart Institute), Alison M. Dunning(University of Cambridge), Douglas F. Easton(University of Cambridge), Todd L. Edwards(Vanderbilt University), David Ellinghaus(Christian-Albrechts-Universität zu Kiel), Patrick T. Ellinor(Broad Institute), Paul Elliott(Imperial College London), Εvangelos Εvangelou(University of Ioannina), Aliki‐Eleni Farmaki(University of Leicester), I. Sadaf Farooqi(University of Cambridge), Jessica D. Faul(University of Michigan), Sascha Fauser(University of Cologne), Shuang Feng(University of Michigan), Ele Ferrannini(University of Pisa), Jean Ferrières, José C. Florez(Broad Institute), Ian Ford(University of Glasgow), Myriam Fornage(The University of Texas Health Science Center at Houston), Oscar H. Franco(Erasmus MC), André Franke(Christian-Albrechts-Universität zu Kiel), Paul W. Franks(Harvard University), Nele Friedrich(Universitätsmedizin Greifswald), Ruth Frikke‐Schmidt(University of Copenhagen), Tessel E. Galesloot(Radboud University Nijmegen), Wei Gan(Centre for Human Genetics), Ilaria Gandin(AREA Science Park), Paolo Gasparini(University of Trieste), Jane Whitney Gibson(University of Southampton), Vilmantas Giedraitis(Uppsala University), Anette P. Gjesing(University of Copenhagen), Penny Gordon‐Larsen(University of North Carolina at Chapel Hill), Mathias Gorski(University Hospital Regensburg), Hans J. Grabe(Universitätsmedizin Greifswald), Struan F.A. Grant(Children's Hospital of Philadelphia), Niels Grarup(University of Copenhagen), Helen Griffiths(University of Southampton), Megan L. Grove(The University of Texas Health Science Center at Houston), Vilmundur Guðnason(University of Iceland), Stefan Gustafsson(Uppsala University), Jeff Haessler(Fred Hutch Cancer Center), Håkon Håkonarson(Children's Hospital of Philadelphia), Anke R. Hammerschlag(Amsterdam Neuroscience), Torben Hansen(University of Copenhagen), Kathleen Mullan Harris(University of North Carolina at Chapel Hill), Tamara B. Harris(National Institutes of Health), Andrew T. Hattersley(University of Exeter), Christian T. Have(University of Copenhagen), Caroline Hayward(Institute of Genetics and Cancer), Liang He(Social Science Research Council), Nancy L. Heard‐Costa(Boston University), Andrew C. Heath(Washington University in St. Louis), Iris M. Heid(Helmholtz Zentrum München), Øyvind Helgeland(Haukeland University Hospital), Jussi Hernesniemi(Tampere University), Alex W. Hewitt(Lions Eye Institute), Oddgeir L. Holmen(Norwegian University of Science and Technology), G. Kees Hovingh, Joanna M. M. Howson(University of Cambridge), Yao Hu(Chinese Academy of Sciences), Paul L. Huang(Massachusetts General Hospital), Jennifer E. Huffman(Institute of Genetics and Cancer), M. Arfan Ikram(Erasmus MC), Erik Ingelsson(Uppsala University), Anne Jackson(University of Michigan), Jan‐Håkan Jansson(Skellefteå Hospital), Gail P. Jarvik(University of Washington), Gorm Boje Jensen(Frederiksberg Hospital), Yucheng Jia(The Lundquist Institute), Stefan Johansson(Haukeland University Hospital), Marit E. Jørgensen(Steno Diabetes Centers), Torben Jørgensen(University of Copenhagen), J. Wouter Jukema(Leiden University Medical Center), Bratati Kahali(University of Michigan), René S. Kahn(University Medical Center Utrecht), Mika Kähönen(Tampere University), Pia R. Kamstrup(Gentofte Hospital), Stavroula Kanoni(Queen Mary University of London), Jaakko Kaprio(University of Helsinki), Maria Karaleftheri(Athens Medical Center), Sharon L. R. Kardia(University of Michigan), Fredrik Karpe(University of Oxford), Sekar Kathiresan(Broad Institute), Frank Kee(Queen's University Belfast), Lambertus A. Kiemeney(Radboud University Nijmegen), Eric H. Kim(The Lundquist Institute), Hidetoshi Kitajima(Centre for Human Genetics), Pirjo Komulainen(University of Eastern Finland), Jaspal S. Kooner(Imperial College Healthcare NHS Trust), Charles Kooperberg(Fred Hutch Cancer Center), Tellervo Korhonen(University of Helsinki), Péter Kovács(IFB Adiposity Diseases), Helena Kuivaniemi(Stellenbosch University), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Kari Kuulasmaa(Finnish Institute for Health and Welfare), Johanna Kuusisto(University of Eastern Finland), Markku Laakso(University of Eastern Finland), Timo A. Lakka(University of Eastern Finland), David Lamparter(SIB Swiss Institute of Bioinformatics), Ethan M. Lange(University of North Carolina at Chapel Hill), Leslie A. Lange(University of North Carolina at Chapel Hill), Claudia Langenberg(University of Cambridge), Eric B. Larson(Kaiser Permanente Washington Health Research Institute), Sang Lee(University of San Carlos), Terho Lehtimäki(Tampere University), Cora E. Lewis(University of Alabama at Birmingham), Huaixing Li(Chinese Academy of Sciences), Jin Li(Stanford University), Ruifang Li‐Gao(Leiden University Medical Center), Honghuang Lin(Boston University), Keng‐Hung Lin(Taichung Veterans General Hospital), Li‐An Lin(The University of Texas Health Science Center at Houston), Lin Xu(Chinese Academy of Sciences), Lars Lind(Uppsala University), Jaana Lindström(Finnish Institute for Health and Welfare), Allan Linneberg(University of Copenhagen), Ching‐Ti Liu(Boston University), Dajiang J. Liu(Pennsylvania State University), Ching‐Ti Liu(Wake Forest University), Ken Sin Lo(Montreal Heart Institute), Artitaya Lophatananon(University of Warwick), Andrew Lotery(University of Southampton), Anu Loukola(University of Helsinki), Jian'an Luan(University of Cambridge), Steven A. Lubitz(Broad Institute), Leo‐Pekka Lyytikäinen(Tampere University), Satu Männistö(Finnish Institute for Health and Welfare), Gaëlle Marenne(Wellcome Sanger Institute), Angela L. Mazul(University of North Carolina at Chapel Hill), Mark I. McCarthy(Centre for Human Genetics), Roberta McKean‐Cowdin(University of Southern California), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Karina Meidtner(Deutsches Diabetes-Zentrum e.V.), Lili Milani(University of Tartu), Vanisha Mistry(University of Cambridge), Paul Mitchell(The University of Sydney), Karen L. Mohlke(University of North Carolina at Chapel Hill), Leena Moilanen(Kuopio University Hospital), Marie Moitry(Université de Strasbourg), Grant W. Montgomery(The University of Queensland), Dennis O. Mook‐Kanamori(Leiden University Medical Center), Carmel Moore(University of Cambridge), Trevor A. Mori(The University of Western Australia), Andrew D. Morris(Centre for Human Genetics), Andrew P. Morris(Centre for Human Genetics), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Patricia B. Munroe(Queen Mary University of London), Mike A. Nalls(National Institutes of Health), Narisu Narisu(National Institutes of Health), Christopher P. Nelson(University of Leicester), Matt J. Neville(University of Oxford), Sune F. Nielsen(University of Copenhagen), Kjell Nikus(Tampere University Hospital), Pål R. Njølstad(Haukeland University Hospital), Børge G. Nordestgaard(University of Copenhagen), Dale R. Nyholt(Queensland University of Technology), Jeffrey R. O’Connel(University of Maryland, Baltimore), Michelle L. O’Donoghue(Brigham and Women's Hospital), Loes M. Olde Loohuis(University of California, Los Angeles), Roel A. Ophoff(University of California, Los Angeles), Katharine R. Owen(University of Oxford), Chris J. Packard(University of Glasgow), Sandosh Padmanabhan(University of Glasgow), Colin N. A. Palmer(Ninewells Hospital), Nicholette D. Palmer(Wake Forest University), Gerard Pasterkamp(Utrecht University), Aniruddh P. Patel(Broad Institute), Alison Pattie(University of Edinburgh), Oluf Pedersen(University of Copenhagen), Peggy Peissig(Marshfield Clinic), Gina M. Peloso(Boston University), Craig E. Pennell(The University of Western Australia), Markus Perola(University of Helsinki), James A. Perry(University of Maryland, Baltimore), John R. B. Perry(University of Maryland, Baltimore), Tune H. Pers(Statens Serum Institut), Thomas N. Person(Marshfield Clinic), Annette Peters(Helmholtz Zentrum München), Annette Peters(Lillebaelt Hospital), Patricia A. Peyser(University of Michigan), Ailith Pirie(University of Cambridge), Ozren Polašek(University of Split), Tinca J. C. Polderman(Amsterdam Neuroscience), Hannu Puolijoki, Olli T. Raitakari(University of Turku), Asif Rasheed(Center for Non-Communicable Diseases), Rainer Rauramaa(University of Eastern Finland), Dermot F. Reilly(Merck & Co., Inc., Rahway, NJ, USA (United States)), Frida Renström(Lund University), Myriam Rheinberger(University Hospital Regensburg), Paul M. Ridker(Brigham and Women's Hospital), John D. Rioux(Montreal Heart Institute), Manuel A. Rivas(Broad Institute), David J. Roberts(NHS Blood and Transplant), Neil R. Robertson(Centre for Human Genetics), Antonietta Robino(IRCCS Materno Infantile Burlo Garofolo), Olov Rolandsson(Umeå University), Igor Rudan(University of Edinburgh), Katherine S. Ruth(University of Exeter), Danish Saleheen(Center for Non-Communicable Diseases), Veikko Salomaa(Finnish Institute for Health and Welfare), Nilesh J. Samani(University of Leicester), Yadav Sapkota(QIMR Berghofer Medical Research Institute), Naveed Sattar(University of Glasgow), Robert E. Schoen(University of Pittsburgh Medical Center), Pamela J. Schreiner(University of Minnesota), Matthias B. Schulze(Deutsches Diabetes-Zentrum e.V.), Robert A. Scott(University of Cambridge), Marcelo P. Segura-Lepe(Imperial College London), Svati H. Shah(Duke University), Wayne H-H Sheu(National Yang Ming Chiao Tung University), Xueling Sim(National University of Singapore), Andrew J. Slater(Research Triangle Park Foundation), Kerrin S. Small(King's College London), Albert V. Smith(University of Iceland), Lorraine Southam(Centre for Human Genetics), Timothy D. Spector(King's College London), Elizabeth K. Speliotes(University of Michigan), John M. Starr(Alzheimer Scotland), Kāri Stefánsson(deCODE Genetics (Iceland)), Valgerður Steinthórsdóttir(deCODE Genetics (Iceland)), Kathleen Stirrups(Queen Mary University of London), Konstantin Strauch(Helmholtz Zentrum München), Heather M. Stringham(University of Michigan), Michael Stümvoll(IFB Adiposity Diseases), Liang Sun(Social Science Research Council), Praveen Surendran(University of Cambridge), Amy J. Swift(National Institutes of Health), Hayato Tada(Kanazawa University), Katherine E. Tansey(University of Bristol), Jean‐Claude Tardif(Montreal Heart Institute), Kent D. Taylor(The Lundquist Institute), Alexander Teumer(Universitätsmedizin Greifswald), Deborah J. Thompson(University of Cambridge), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Betina H. Thuesen(Capital Region of Denmark), Anke Tönjes(Leipzig University), Gerard Tromp(Stellenbosch University), Stella Trompet(Leiden University Medical Center), Emmanouil Tsafantakis, Jaakko Tuomilehto(Universität für Weiterbildung Krems), Anne Tybjærg‐Hansen(University of Copenhagen), Jonathan P. Tyrer(University of Cambridge), Rudolf Uher(Dalhousie University), André G. Uitterlinden(Erasmus MC), Matti Uusitupa(University of Eastern Finland), Sander W. van der Laan(University Medical Center Utrecht), Cornelia M. van Duijn(Erasmus MC), Nienke van Leeuwen(Leiden University Medical Center), Jessica van Setten(University Medical Center Utrecht), Mauno Vanhala(Kuopio University Hospital), Anette Varbo(University of Copenhagen), Tibor V. Varga(Lund University), Rohit Varma(University of Southern California), Digna R. Velez Edwards(Vanderbilt University), Sita H. Vermeulen(Radboud University Nijmegen), Giovanni Veronesi(University of Insubria), Henrik Vestergaard(University of Copenhagen), Véronique Vitart(Institute of Genetics and Cancer), Thomas Vogt(Merck & Co., Inc., Rahway, NJ, USA (United States)), Uwe Völker(Universitätsmedizin Greifswald), Dragana Vuckovic(University of Trieste), Lynne E. Wagenknecht(Wake Forest University), Mark Walker(Newcastle University), Lars Wallentin(Uppsala University), Feijie Wang(Chinese Academy of Sciences), Carol A. Wang(The University of Western Australia), Shuai Wang(Boston University), Yiqin Wang(Chinese Academy of Sciences), Erin B. Ware(University of Michigan), Nicholas J. Wareham(University of Cambridge), Helen R. Warren(Queen Mary University of London), Dawn Waterworth(Target (United States)), Jennifer Wessel(Indiana University Indianapolis), Harvey D. White(University of Auckland), Cristen J. Willer(University of Michigan), James G. Wilson(Jackson Memorial Hospital), Daniel R. Witte(Aarhus University), Andrew R. Wood(University of Exeter), Ying Wu(University of North Carolina at Chapel Hill), Hanieh Yaghootkar(University of Exeter), Jie Yao(The Lundquist Institute), Pang Yao(Chinese Academy of Sciences), Laura M. Yerges-Armstrong(University of Maryland, Baltimore), Robin Young(University of Cambridge), Eleftheria Zeggini(Wellcome Sanger Institute), Xiaowei Zhan(The University of Texas Southwestern Medical Center), Weihua Zhang(Ealing Hospital), Wei Zhao(University of Cambridge), Wei Zhao(University of Michigan), Wei Zhao(University of Michigan), Wei Zhou(University of Michigan), Krina T. Zondervan(Centre for Human Genetics), INTERVAL Study(The Lundquist Institute), The MAGIC Investigators(Max Planck Institute of Immunobiology and Epigenetics), Understanding Society Scientific Group(Erasmus MC), Jerome I. Rotter(The Lundquist Institute), J. Andrew Pospisilik(Queen Mary University of London), Fernando Rivadeneira(University of Exeter), Ingrid B. Borecki(Montreal Heart Institute), Panos Deloukas(University of North Carolina at Chapel Hill), Timothy M. Frayling(Centre for Human Genetics), Guillaume Lettre(Broad Institute), Kari E. North(University of North Carolina at Chapel Hill), Cecilia M. Lindgren(Centre for Human Genetics), Joel N. Hirschhorn(Broad Institute), Ruth J. F. Loos(Child Health and Development Institute)
Cited by 427Open Access
Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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