Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-01

AUTHORS

Valérie Turcot, Yingchang Lu, Heather M Highland, Claudia Schurmann, Anne E Justice, Rebecca S Fine, Jonathan P Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L Young, Tamuno Alfred, Mary F Feitosa, Nicholas GD Masca, Alisa K Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie CY Ng, Alex P Reiner, Sailaja Vedantam, Sara M Willems, Thomas W Winkler, Goncalo Abecasis, Katja K Aben, Dewan S Alam, Sameer E Alharthi, Matthew Allison, Philippe Amouyel, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Lia E Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A Böger, Jette Bork-Jensen, Michiel L Bots, Erwin P Bottinger, Donald W Bowden, Ivan Brandslund, Gerome Breen, Murray H Brilliant, Linda Broer, Marco Brumat, Amber A Burt, Adam S Butterworth, Peter T Campbell, Stefania Cappellani, David J Carey, Eulalia Catamo, Mark J Caulfield, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, Massimiliano Cocca, Francis S Collins, James P Cook, Janie Corley, Jordi Corominas Galbany, Amanda J Cox, David S Crosslin, Gabriel Cuellar-Partida, Angela D'Eustacchio, John Danesh, Gail Davies, Paul IW de Bakker, Mark CH de Groot, Renée de Mutsert, Ian J Deary, George Dedoussis, Ellen W Demerath, Martin den Heijer, Anneke I den Hollander, Hester M den Ruijter, Joe G Dennis, Josh C Denny, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Marie-Pierre Dubé, Alison M Dunning, Douglas F Easton, Todd L Edwards, David Ellinghaus, Patrick T Ellinor, Paul Elliott, Evangelos Evangelou, Aliki-Eleni Farmaki, I. Sadaf Farooqi, Jessica D Faul, Sascha Fauser, Shuang Feng, Ele Ferrannini, Jean Ferrieres, Jose C Florez, Ian Ford, Myriam Fornage, Oscar H Franco, Andre Franke, Paul W Franks, Nele Friedrich, Ruth Frikke-Schmidt, Tessel E. Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Jane Gibson, Vilmantas Giedraitis, Anette P Gjesing, Penny Gordon-Larsen, Mathias Gorski, Hans-Jörgen Grabe, Struan FA Grant, Niels Grarup, Helen L Griffiths, Megan L Grove, Vilmundur Gudnason, Stefan Gustafsson, Jeff Haessler, Hakon Hakonarson, Anke R Hammerschlag, Torben Hansen, Kathleen Mullan Harris, Tamara B Harris, Andrew T Hattersley, Christian T Have, Caroline Hayward, Liang He, Nancy L Heard-Costa, Andrew C Heath, Iris M Heid, Øyvind Helgeland, Jussi Hernesniemi, Alex W Hewitt, Oddgeir L Holmen, G Kees Hovingh, Joanna MM Howson, Yao Hu, Paul L Huang, Jennifer E Huffman, M Arfan Ikram, Erik Ingelsson, Anne U Jackson, Jan-Håkan Jansson, Gail P Jarvik, Gorm B Jensen, Yucheng Jia, Stefan Johansson, Marit E Jørgensen, Torben Jørgensen, J Wouter Jukema, Bratati Kahali, René S Kahn, Mika Kähönen, Pia R Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon LR Kardia, Fredrik Karpe, Sekar Kathiresan, Frank Kee, Lambertus A Kiemeney, Eric Kim, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S Kooner, Charles Kooperberg, Tellervo Korhonen, Peter Kovacs, Helena Kuivaniemi, Zoltán Kutalik, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A Lakka, David Lamparter, Ethan M Lange, Leslie A Lange, Claudia Langenberg, Eric B Larson, Nanette R Lee, Terho Lehtimäki, Cora E Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Honghuang Lin, Keng-Hung Lin, Li-An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Dajiang J Liu, Yongmei Liu, Ken Sin Lo, Artitaya Lophatananon, Andrew J Lotery, Anu Loukola, Jian'an Luan, Steven A Lubitz, Leo-Pekka Lyytikäinen, Satu Männistö, Gaëlle Marenne, Angela L Mazul, Mark I McCarthy, Roberta McKean-Cowdin, Sarah E Medland, Karina Meidtner, Lili Milani, Vanisha Mistry, Paul Mitchell, Karen L Mohlke, Leena Moilanen, Marie Moitry, Grant W Montgomery, Dennis O Mook-Kanamori, Carmel Moore, Trevor A Mori, Andrew D Morris, Andrew P Morris, Martina Müller-Nurasyid, Patricia B Munroe, Mike A Nalls, Narisu Narisu, Christopher P Nelson, Matt Neville, Sune F Nielsen, Kjell Nikus, Pål R Njølstad, Børge G Nordestgaard, Dale R Nyholt, Jeffrey R O'Connel, Michelle L. O’Donoghue, Loes M Olde Loohuis, Roel A Ophoff, Katharine R Owen, Chris J Packard, Sandosh Padmanabhan, Colin NA Palmer, Nicholette D Palmer, Gerard Pasterkamp, Aniruddh P Patel, Alison Pattie, Oluf Pedersen, Peggy L Peissig, Gina M Peloso, Craig E Pennell, Markus Perola, James A Perry, John RB Perry, Tune H Pers, Thomas N Person, Annette Peters, Eva RB Petersen, Patricia A Peyser, Ailith Pirie, Ozren Polasek, Tinca J Polderman, Hannu Puolijoki, Olli T Raitakari, Asif Rasheed, Rainer Rauramaa, Dermot F Reilly, Frida Renström, Myriam Rheinberger, Paul M Ridker, John D Rioux, Manuel A Rivas, David J Roberts, Neil R Robertson, Antonietta Robino, Olov Rolandsson, Igor Rudan, Katherine S Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Yadav Sapkota, Naveed Sattar, Robert E Schoen, Pamela J Schreiner, Matthias B Schulze, Robert A Scott, Marcelo P Segura-Lepe, Svati H Shah, Wayne H-H Sheu, Xueling Sim, Andrew J Slater, Kerrin S Small, Albert Vernon Smith, Lorraine Southam, Timothy D Spector, Elizabeth K Speliotes, John M Starr, Kari Stefansson, Valgerdur Steinthorsdottir, Kathleen E Stirrups, Konstantin Strauch, Heather M Stringham, Michael Stumvoll, Liang Sun, Praveen Surendran, Amy J Swift, Hayato Tada, Katherine E Tansey, Jean-Claude Tardif, Kent D Taylor, Alexander Teumer, Deborah J Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Betina H Thuesen, Anke Tönjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Jonathan P Tyrer, Rudolf Uher, André G Uitterlinden, Matti Uusitupa, Sander W van der Laan, Cornelia M van Duijn, Nienke van Leeuwen, Jessica van Setten, Mauno Vanhala, Anette Varbo, Tibor V Varga, Rohit Varma, Digna R Velez Edwards, Sita H Vermeulen, Giovanni Veronesi, Henrik Vestergaard, Veronique Vitart, Thomas F Vogt, Uwe Völker, Dragana Vuckovic, Lynne E Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A Wang, Shuai Wang, Yiqin Wang, Erin B Ware, Nicholas J Wareham, Helen R Warren, Dawn M Waterworth, Jennifer Wessel, Harvey D White, Cristen J Willer, James G Wilson, Daniel R Witte, Andrew R Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Pang Yao, Laura M Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, Wei Zhao, Wei Zhou, Krina T Zondervan, , Jerome I Rotter, John A Pospisilik, Fernando Rivadeneira, Ingrid B Borecki, Panos Deloukas, Timothy M Frayling, Guillaume Lettre, Kari E North, Cecilia M Lindgren, Joel N Hirschhorn, Ruth JF Loos

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. More... »

PAGES

26-41

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    1

    VOLUME

    50

    Author Affiliations

  • Icahn School of Medicine at Mount Sinai
  • The University of Texas Health Science Center at Houston
  • University of North Carolina System
  • Boston Children's Hospital
  • Children's Hospital of Philadelphia
  • University of Tartu
  • Vanderbilt University
  • Harbor–UCLA Medical Center
  • University of Colorado Denver
  • Eastern Mediterranean University
  • Max Planck Institute of Immunobiology and Epigenetics
  • Washington University in St. Louis
  • Wellcome Centre for Human Genetics
  • Queen Mary University of London
  • University of Cambridge
  • Glenfield Hospital
  • Broad Institute
  • Erasmus University Medical Center
  • Wake Forest University
  • Fred Hutchinson Cancer Research Center
  • Institute of Metabolic Science
  • University of Regensburg
  • University of Michigan–Ann Arbor
  • Radboud University Nijmegen Medical Centre
  • York University
  • King Abdulaziz University
  • University of California, San Diego
  • Lille 1 University
  • University College London
  • University of Wisconsin–Milwaukee
  • Centre for research in epidemiology and population health
  • Addenbrooke's Hospital
  • University of Copenhagen
  • Swiss Institute of Bioinformatics
  • Leipzig University
  • German Institute of Human Nutrition
  • Baylor College of Medicine
  • University Hospital Regensburg
  • University Medical Center Utrecht
  • University of Southern Denmark
  • NIHR Maudsley Dementia Biomedical Research Unit
  • Marshfield Clinic
  • University of Trieste
  • University of Washington
  • American Cancer Society
  • IRCCS Materno Infantile Burlo Garofolo
  • Geisinger Medical Center
  • Imperial College Healthcare NHS Trust
  • Harvard University
  • Sygehus Lillebælt
  • Brigham and Women's Hospital
  • National Human Genome Research Institute
  • University of Liverpool
  • University of Edinburgh
  • Griffith University
  • QIMR Berghofer Medical Research Institute
  • Utrecht University
  • Leiden University Medical Center
  • Harokopio University
  • University of Minnesota
  • VU University Medical Center
  • University of Bristol
  • Memorial Sloan Kettering Cancer Center
  • University of Montreal
  • Kiel University
  • Imperial College London
  • University of Ioannina
  • University of Leicester
  • University of Cologne
  • University of Pisa
  • University of Toulouse
  • University of Glasgow
  • Umeå University
  • University of Greifswald
  • AREA Science Park
  • University of Southampton
  • Uppsala University
  • University of North Carolina at Chapel Hill
  • German Center for Neurodegenerative Diseases
  • Icelandic Heart Association
  • University of Pennsylvania
  • Amsterdam Neuroscience
  • National Institutes of Health
  • University of Exeter
  • University of Helsinki
  • Boston University School of Medicine
  • Helmholtz Zentrum München
  • University of Bergen
  • University of Tampere
  • University of Tasmania
  • Norwegian University of Science and Technology
  • Academic Medical Center
  • Shanghai Institutes for Biological Sciences
  • Massachusetts General Hospital
  • Stanford University
  • Frederiksberg Hospital
  • Haukeland University Hospital
  • Steno Diabetes Center
  • Capital Region of Denmark
  • Netherlands Heart Institute
  • Indian Institute of Science Bangalore
  • Tampere University Hospital
  • National Institute for Health and Welfare
  • NIHR Oxford Musculoskeletal Biomedical Research Unit
  • Queen's University Belfast
  • Kuopio University Hospital
  • Stellenbosch University
  • Institute of Social and Preventive Medicine
  • University of San Carlos
  • University of Alabama at Birmingham
  • Taichung Veterans General Hospital
  • Boston University
  • Pennsylvania State University
  • University of Warwick
  • Wellcome Sanger Institute
  • University of California Los Angeles
  • German Center for Diabetes Research
  • University of Sydney
  • Hôpitaux Universitaires de Strasbourg
  • University of Queensland
  • University of Western Australia
  • German Centre for Cardiovascular Research
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
  • Queensland University of Technology
  • University of Maryland, Baltimore
  • Ninewells Hospital
  • Statens Serum Institut
  • University of Split
  • Seinäjoen Keskussairaala
  • University of Turku
  • MSD (United States)
  • University of Oxford
  • University of Pittsburgh Medical Center
  • Duke University
  • National Yang Ming University
  • National University of Singapore
  • King's College London
  • University of Iceland
  • Ludwig Maximilian University of Munich
  • Kanazawa University
  • Cardiff University
  • Dalhousie University
  • University of Eastern Finland
  • Central Finland Health Care District
  • Lund University
  • University of Southern California
  • University of Insubria
  • Newcastle University
  • GlaxoSmithKline (United States)
  • Indiana University of Pennsylvania
  • University of Auckland
  • University of Mississippi Medical Center
  • Aarhus University
  • The University of Texas Southwestern Medical Center
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-017-0011-x

    DOI

    http://dx.doi.org/10.1038/s41588-017-0011-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1099876841

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29273807


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