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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Justice, Anne E; Karaderi, Tugce; Highland, Heather M; Young, Kristin L; Graff, Mariaelisa; Lu, Yingchang; Turcot, Valérie; Auer, Paul L; Fine, Rebecca S; Guo, Xiuqing; Schurmann, Claudia; Lempradl, Adelheid; Marouli, Eirini; Mahajan, Anubha; Winkler, Thomas W; Locke, Adam E; Medina-Gomez, Carolina; Esko, Tõnu; Vedantam, Sailaja; Giri, Ayush; Lo, Ken Sin; Alfred, Tamuno; Mudgal, Poorva; Ng, Maggie C Y; Heard-Costa, Nancy L; Feitosa, Mary F; Manning, Alisa K; Willems, Sara M; Sivapalaratnam, Suthesh; Abecasis, Goncalo; Alam, Dewan S; Allison, Matthew; Amouyel, Philippe; Arzumanyan, Zorayr; Balkau, Beverley; Bastarache, Lisa; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Broer, Linda; Burt, Amber A; Butterworth, Adam S.
Affiliation
  • Justice AE; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
  • Karaderi T; Weis Center for Research, Geisinger Health System, Danville, PA, USA.
  • Highland HM; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Young KL; Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus.
  • Graff M; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
  • Lu Y; 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.
  • Turcot V; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
  • Auer PL; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
  • Fine RS; Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Guo X; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Schurmann C; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Lempradl A; Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada.
  • Marouli E; Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
  • Mahajan A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Winkler TW; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Locke AE; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
  • Medina-Gomez C; Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
  • Esko T; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Vedantam S; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Giri A; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • Lo KS; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Alfred T; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Mudgal P; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  • Ng MCY; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Heard-Costa NL; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA.
  • Feitosa MF; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Manning AK; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Willems SM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sivapalaratnam S; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
  • Abecasis G; Estonian Genome Center, University of Tartu, Tartu, Estonia.
  • Alam DS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Allison M; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Amouyel P; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
  • Arzumanyan Z; Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
  • Balkau B; Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada.
  • Bastarache L; Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
  • Bergmann S; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Bielak LF; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Blüher M; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Boehnke M; Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Boeing H; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
  • Boerwinkle E; NHLBI Framingham Heart Study, Framingham, MA, USA.
  • Böger CA; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • Bork-Jensen J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bottinger EP; Department of Medicine, Harvard University Medical School, Boston, MA, USA.
  • Bowden DW; Massachusetts General Hospital, Boston, MA, USA.
  • Brandslund I; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
  • Broer L; Massachusetts General Hospital, Boston, MA, USA.
  • Burt AA; Department of Vascular Medicine, AMC, Amsterdam, The Netherlands.
  • Butterworth AS; Department of Haematology, University of Cambridge, Cambridge, UK.
Nat Genet ; 51(3): 452-469, 2019 03.
Article in En | MEDLINE | ID: mdl-30778226
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Variation / Proteins / Genetic Predisposition to Disease / Homeostasis / Lipids Type of study: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Animals / Female / Humans / Male Language: En Journal: Nat Genet Year: 2019 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Variation / Proteins / Genetic Predisposition to Disease / Homeostasis / Lipids Type of study: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Animals / Female / Humans / Male Language: En Journal: Nat Genet Year: 2019 Document type: Article