Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-03

AUTHORS

Anne E. Justice, Tugce Karaderi, Heather M. Highland, Kristin L. Young, Mariaelisa Graff, Yingchang Lu, Valérie Turcot, Paul L. Auer, Rebecca S. Fine, Xiuqing Guo, Claudia Schurmann, Adelheid Lempradl, Eirini Marouli, Anubha Mahajan, Thomas W. Winkler, Adam E. Locke, Carolina Medina-Gomez, Tõnu Esko, Sailaja Vedantam, Ayush Giri, Ken Sin Lo, Tamuno Alfred, Poorva Mudgal, Maggie C. Y. Ng, Nancy L. Heard-Costa, Mary F. Feitosa, Alisa K. Manning, Sara M. Willems, Suthesh Sivapalaratnam, Goncalo Abecasis, Dewan S. Alam, Matthew Allison, Philippe Amouyel, Zorayr Arzumanyan, Beverley Balkau, Lisa Bastarache, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Jette Bork-Jensen, Erwin P. Bottinger, Donald W. Bowden, Ivan Brandslund, Linda Broer, Amber A. Burt, Adam S. Butterworth, Mark J. Caulfield, Giancarlo Cesana, John C. Chambers, Daniel I. Chasman, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, Francis S. Collins, James P. Cook, Amanda J. Cox, David S. Crosslin, John Danesh, Paul I. W. de Bakker, Simon de Denus, Renée de Mutsert, George Dedoussis, Ellen W. Demerath, Joe G. Dennis, Josh C. Denny, Emanuele Di Angelantonio, Marcus Dörr, Fotios Drenos, Marie-Pierre Dubé, Alison M. Dunning, Douglas F. Easton, Paul Elliott, Evangelos Evangelou, Aliki-Eleni Farmaki, Shuang Feng, Ele Ferrannini, Jean Ferrieres, Jose C. Florez, Myriam Fornage, Caroline S. Fox, Paul W. Franks, Nele Friedrich, Wei Gan, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Giorgia Girotto, Mathias Gorski, Harald Grallert, Niels Grarup, Megan L. Grove, Stefan Gustafsson, Jeff Haessler, Torben Hansen, Andrew T. Hattersley, Caroline Hayward, Iris M. Heid, Oddgeir L. Holmen, G. Kees Hovingh, Joanna M. M. Howson, Yao Hu, Yi-Jen Hung, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne U. Jackson, Gail P. Jarvik, Yucheng Jia, Torben Jørgensen, Pekka Jousilahti, Johanne M. Justesen, Bratati Kahali, Maria Karaleftheri, Sharon L. R. Kardia, Fredrik Karpe, Frank Kee, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S. Kooner, Peter Kovacs, Bernhard K. Krämer, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, David Lamparter, Leslie A. Lange, Claudia Langenberg, Eric B. Larson, Nanette R. Lee, Wen-Jane Lee, Terho Lehtimäki, Cora E. Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Li-An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Dajiang J. Liu, Jian’an Luan, Leo-Pekka Lyytikäinen, Stuart MacGregor, Reedik Mägi, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas G. D. Masca, Mark I. McCarthy, Karina Meidtner, Evelin Mihailov, Leena Moilanen, Marie Moitry, Dennis O. Mook-Kanamori, Anna Morgan, Andrew P. Morris, Martina Müller-Nurasyid, Patricia B. Munroe, Narisu Narisu, Christopher P. Nelson, Matt Neville, Ioanna Ntalla, Jeffrey R. O’Connell, Katharine R. Owen, Oluf Pedersen, Gina M. Peloso, Craig E. Pennell, Markus Perola, James A. Perry, John R. B. Perry, Tune H. Pers, Ailith Ewing, Ozren Polasek, Olli T. Raitakari, Asif Rasheed, Chelsea K. Raulerson, Rainer Rauramaa, Dermot F. Reilly, Alex P. Reiner, Paul M. Ridker, Manuel A. Rivas, Neil R. Robertson, Antonietta Robino, Igor Rudan, Katherine S. Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Pamela J. Schreiner, Matthias B. Schulze, Robert A. Scott, Marcelo Segura-Lepe, Xueling Sim, Andrew J. Slater, Kerrin S. Small, Blair H. Smith, Jennifer A. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, Kari Stefansson, Valgerdur Steinthorsdottir, Kathleen E. Stirrups, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Liang Sun, Praveen Surendran, Karin M. A. Swart, Jean-Claude Tardif, Kent D. Taylor, Alexander Teumer, Deborah J. Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Betina H. Thuesen, Anke Tönjes, Mina Torres, Emmanouil Tsafantakis, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Cornelia M. van Duijn, Mauno Vanhala, Rohit Varma, Sita H. Vermeulen, Henrik Vestergaard, Veronique Vitart, Thomas F. Vogt, Dragana Vuckovic, Lynne E. Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A. Wang, Shuai Wang, Nicholas J. Wareham, Helen R. Warren, Dawn M. Waterworth, Jennifer Wessel, Harvey D. White, Cristen J. Willer, James G. Wilson, Andrew R. Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Laura M. Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, He Zheng, Wei Zhou, M. Carola Zillikens, Fernando Rivadeneira, Ingrid B. Borecki, J. Andrew Pospisilik, Panos Deloukas, Timothy M. Frayling, Guillaume Lettre, Karen L. Mohlke, Jerome I. Rotter, Zoltán Kutalik, Joel N. Hirschhorn, L. Adrienne Cupples, Ruth J. F. Loos, Kari E. North, Cecilia M. Lindgren

ABSTRACT

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants. More... »

PAGES

452-469

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    3

    VOLUME

    51

    Author Affiliations

  • Geisinger Medical Center
  • Eastern Mediterranean University
  • The University of Texas Health Science Center at Houston
  • University of North Carolina System
  • Icahn School of Medicine at Mount Sinai
  • University of Wisconsin–Milwaukee
  • Boston Children's Hospital
  • Harbor–UCLA Medical Center
  • Max Planck Institute of Immunobiology and Epigenetics
  • Queen Mary University of London
  • Wellcome Centre for Human Genetics
  • University of Regensburg
  • Washington University in St. Louis
  • Erasmus University Medical Center
  • University of Tartu
  • Vanderbilt University
  • Wake Forest University
  • Boston University School of Medicine
  • Massachusetts General Hospital
  • Institute of Metabolic Science
  • University of Cambridge
  • University of Michigan–Ann Arbor
  • York University
  • University of California, San Diego
  • Lille 1 University
  • Centre for research in epidemiology and population health
  • Swiss Institute of Bioinformatics
  • Leipzig University
  • German Institute of Human Nutrition
  • Baylor College of Medicine
  • University Hospital Regensburg
  • University of Copenhagen
  • University of Southern Denmark
  • University of Washington
  • University of Milano-Bicocca
  • Imperial College London
  • Harvard University
  • Sygehus Lillebælt
  • Brigham and Women's Hospital
  • National Human Genome Research Institute
  • University of Liverpool
  • Griffith University
  • University Medical Center Utrecht
  • University of Montreal
  • Leiden University Medical Center
  • Harokopio University
  • University of Minnesota
  • German Centre for Cardiovascular Research
  • Brunel University London
  • University of Ioannina
  • University of Pisa
  • University of Toulouse
  • Umeå University
  • University of Greifswald
  • AREA Science Park
  • IRCCS Materno Infantile Burlo Garofolo
  • Uppsala University
  • German Center for Diabetes Research
  • Fred Hutchinson Cancer Research Center
  • University of Exeter
  • University of Edinburgh
  • Norwegian University of Science and Technology
  • Academic Medical Center
  • Shanghai Institutes for Biological Sciences
  • National Defense Medical Center
  • Stanford University
  • Capital Region of Denmark
  • National Institute for Health and Welfare
  • Indian Institute of Science Bangalore
  • NIHR Oxford Musculoskeletal Biomedical Research Unit
  • Queen's University Belfast
  • Kuopion Liikuntalääketieteen Tutkimuslaitos
  • University Medical Centre Mannheim
  • Kuopio University Hospital
  • University of Colorado Anschutz Medical Campus
  • University of San Carlos
  • Tunghai University
  • University of Tampere
  • University of Alabama at Birmingham
  • Boston University
  • Pennsylvania State University
  • QIMR Berghofer Medical Research Institute
  • Wellcome Sanger Institute
  • Glenfield Hospital
  • Hôpitaux Universitaires de Strasbourg
  • University of Trieste
  • University of Maryland, Baltimore
  • University of Newcastle Australia
  • University of Helsinki
  • Statens Serum Institut
  • University of Turku
  • University of North Carolina at Chapel Hill
  • University of Eastern Finland
  • MSD (United States)
  • University of Oxford
  • University of Pennsylvania
  • National University of Singapore
  • GlaxoSmithKline (United States)
  • King's College London
  • University of Iceland
  • Ludwig Maximilian University of Munich
  • VU University Medical Center
  • University of Southern California
  • King Abdulaziz University
  • Radboud University Nijmegen Medical Centre
  • Steno Diabetes Center
  • Newcastle University
  • Indiana University of Pennsylvania
  • University of Auckland
  • University of Mississippi Medical Center
  • University of Glasgow
  • The University of Texas Southwestern Medical Center
  • Institute of Social and Preventive Medicine
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-018-0334-2

    DOI

    http://dx.doi.org/10.1038/s41588-018-0334-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112200068

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30778226


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