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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-02-18

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

  • Weis Center for Research, Geisinger Health System, Danville, PA, USA
  • Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus
  • Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
  • Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
  • The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada
  • Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
  • Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA
  • Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA
  • Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
  • William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
  • McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
  • Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  • Estonian Genome Center, University of Tartu, Tartu, Estonia
  • Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
  • Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
  • NHLBI Framingham Heart Study, Framingham, MA, USA
  • Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
  • Massachusetts General Hospital, Boston, MA, USA
  • MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK
  • Department of Haematology, University of Cambridge, Cambridge, UK
  • School of Public Health, University of Michigan, Ann Arbor, MI, USA
  • School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada
  • Department of Family Medicine & Public Health, University of California, San Diego, La Jolla, CA, USA
  • U1167—RID-AGE, Universite de Lille - Risk factors and molecular determinants of aging-related diseases, Lille, France
  • INSERM U1018, Centre de recherche en Épidemiologie et Sante des Populations (CESP), Villejuif, France
  • Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA
  • Swiss Institute of Bioinformatics, Lausanne, Switzerland
  • Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
  • Department of Medicine, University of Leipzig, Leipzig, Germany
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
  • Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
  • Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
  • Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
  • Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
  • Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA
  • NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
  • Research Centre on Public Health, University of Milano-Bicocca, Monza, Italy
  • MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
  • Harvard Medical School, Boston, MA, USA
  • MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • Medical department, Lillebaelt Hospital, Vejle, Denmark
  • Division of Preventive Medicine, Brigham and Women’s and Harvard Medical School, Boston, MA, USA
  • Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Department of Biostatistics, University of Liverpool, Liverpool, UK
  • Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia
  • Department of Biomedical Infomatics and Medical Education, University of Washington, Seattle, WA, USA
  • British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK
  • Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
  • Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada
  • Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  • Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
  • Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
  • Department of Life Sciences, Brunel University London, Uxbridge, UK
  • Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
  • Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
  • Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy
  • Toulouse University School of Medicine, Toulouse, France
  • Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
  • Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden
  • Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
  • Ilaria Gandin, Research Unit, AREA Science Park, Trieste, Italy
  • Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
  • Geriatrics, Department of Public Health, Uppsala University, Uppsala, Sweden
  • Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
  • Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle WA, USA
  • University of Exeter Medical School, University of Exeter, Exeter, UK
  • MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  • Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
  • K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
  • Department of Vascular Medicine, AMC, Amsterdam, The Netherlands
  • CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
  • School of Medicine, National Defense Medical Center, Taipei, Taiwan
  • HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, Levanger, Norway
  • Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
  • Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
  • Department of Genome Sciences, University of Washington, Seattle, WA, USA
  • Research Center for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark
  • National Institute for Health and Welfare, Helsinki, Finland
  • Centre for Brain Research, Indian Institute of Science, Bangalore, India
  • Echinos Medical Centre, Echinos, Greece
  • Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK
  • UKCRC Centre of Excellence for Public Health Research, Queens University Belfast, Belfast, UK
  • Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
  • National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
  • IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany
  • University Medical Centre Mannheim, 5th Medical Department, University of Heidelberg, Mannheim, Germany
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  • Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
  • Verge Genomics, San Fransico, CA, USA
  • Division of Biomedical and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Aurora, CO, USA
  • Department of Health Services, University of Washington, Seattle, WA, USA
  • USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines
  • Department of Social Work, Tunghai University, Taichung, Taiwan
  • Department of Clinical Chemistry, Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
  • Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
  • Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
  • Uppsala University, Uppsala, Sweden
  • Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
  • Department of Public Health Sciences, Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA
  • QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Wellcome Trust Sanger Institute, Hinxton, UK
  • NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
  • Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
  • Department of Medicine, Kuopio University Hospital, Kuopio, Finland
  • Department of Public Health, University Hospital of Strasbourg, Strasbourg, France
  • Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
  • Department of Medical Sciences, University of Trieste, Trieste, Italy
  • DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
  • Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
  • School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, New South Wales, Australia
  • Institute for Molecular Medicine (FIMM) and Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
  • Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  • Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
  • Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
  • Centre for Non-Communicable Diseases, Karachi, Pakistan
  • Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
  • Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland
  • Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA, USA
  • Department of Epidemiology, University of Washington, Seattle, WA, USA
  • Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  • Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  • Institute for Maternal and Child Health, IRCCS ‘Burlo Garofolo’, Trieste, Italy
  • Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
  • Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  • Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore
  • OmicSoft a QIAGEN Company, Cary, NC, USA
  • Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
  • Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK
  • Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
  • Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • deCODE Genetics/Amgen Inc., Reykjavik, Iceland
  • Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany
  • Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
  • Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  • Center for Pediatric Research, Department for Women’s and Child Health, University of Leipzig, Leipzig, Germany
  • USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
  • Anogia Medical Centre, Anogia, Greece
  • Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
  • Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  • Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  • University of Eastern Finland, Kuopio, Finland
  • Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ, USA
  • Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
  • Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK
  • Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  • Genetics, Target Sciences, GlaxoSmithKline, Collegeville, PA, USA
  • Departments of Epidemiology & Medicine, Diabetes Translational Research Center, Fairbanks School of Public Health & School of Medicine, Indiana University, Indiana, IN, USA
  • Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland, New Zealand
  • Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
  • Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
  • GlaxoSmithKline, King of Prussia, PA, USA
  • University of Glasgow, Glasgow, UK
  • Department of Clinical Sciences, Quantitative Biomedical Research Center, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA
  • Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
  • Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
  • Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
  • Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA
  • The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford, UK
  • 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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    62 schema:description 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.
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    69 European ancestry individuals
    70 adiponectin
    71 adipose tissue physiology
    72 analysis
    73 ancestry
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    75 association
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    78 bone development
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