Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Jason Flannick, Broad Institute, Boston Children's Hospital, Harvard Medical School
  • ,
  • Josep M. Mercader, Broad Institute, Massachusetts General Hospital, Boston, Harvard Medical School
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  • Christian Fuchsberger, EURAC Research, University of Michigan, Ann Arbor, Michigan.
  • ,
  • Miriam S. Udler, Broad Institute, Massachusetts General Hospital, Boston, Harvard Medical School
  • ,
  • Anubha Mahajan, The University of Oxford
  • ,
  • Jennifer Wessel, Indiana University
  • ,
  • Tanya M. Teslovich, Regeneron Pharmaceuticals, Inc.
  • ,
  • Lizz Caulkins, Broad Institute
  • ,
  • Ryan Koesterer, Broad Institute
  • ,
  • Francisco Barajas-Olmos, Instituto Nacional de Medicina Genómica Mexico
  • ,
  • Thomas W. Blackwell, University of Michigan, Ann Arbor, Michigan.
  • ,
  • Eric Boerwinkle, University of Texas School of Public Health, Baylor College of Medicine
  • ,
  • Jennifer A. Brody, University of Washington, Seattle
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  • Federico Centeno-Cruz, Instituto Nacional de Medicina Genómica Mexico
  • ,
  • Ling Chen, Massachusetts General Hospital, Boston, Harvard Medical School
  • ,
  • Siying Chen, University of Michigan, Ann Arbor, Michigan.
  • ,
  • Cecilia Contreras-Cubas, Instituto Nacional de Medicina Genómica Mexico
  • ,
  • Emilio Córdova, Instituto Nacional de Medicina Genómica Mexico
  • ,
  • Adolfo Correa, University of Mississippi Medical Center
  • ,
  • Maria Cortes, Broad Institute
  • ,
  • Ralph A. DeFronzo, University of Texas Health Science Center at San Antonio
  • ,
  • Lawrence Dolan, Cincinnati Children's Hospital Medical Center
  • ,
  • Kimberly L. Drews, George Washington University
  • ,
  • Amanda Elliott, Broad Institute, Massachusetts General Hospital, Boston, Harvard Medical School
  • ,
  • James S. Floyd, University of Washington, Seattle
  • ,
  • Stacey Gabriel, Broad Institute
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  • Maria Eugenia Garay-Sevilla, University of Chicago, Chicago, Illinois.
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  • Humberto García-Ortiz, Instituto Nacional de Medicina Genómica Mexico
  • ,
  • Myron Gross, University of Minnesota Twin Cities
  • ,
  • Sohee Han, National Institute of Health
  • ,
  • Nancy L. Heard-Costa, Boston University School of Medicine, National Heart Lung and Blood Institute’s Framingham Heart Study
  • ,
  • Anne U. Jackson, University of Michigan, Ann Arbor, Michigan.
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  • Marit E. Jørgensen, Steno Diabetes Center, University of Greenland, National Institute of Public Health, University of Southern Denmark
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  • Hyun Min Kang, University of Michigan, Ann Arbor, Michigan.
  • ,
  • Megan Kelsey, George Washington University
  • ,
  • Bong Jo Kim, National Institute of Health
  • ,
  • Heikki A. Koistinen, The National Institute for Health and Welfare, Helsingin yliopisto, Minerva Foundation Institute for Medical Research Helsinki
  • ,
  • Johanna Kuusisto, University of Eastern Finland, Division of Cardiology, Kuopio University Central Hospital
  • ,
  • Joseph B. Leader, Geisinger Health System
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  • Allan Linneberg, Københavns Universitet, Frederiksberg Hospital, Rigshospitalet
  • ,
  • Ching Ti Liu, Boston University School of Public Health
  • ,
  • Jianjun Liu, Agency for Science Technology and Research, National University of Singapore
  • ,
  • Valeriya Lyssenko, Lunds Universitet, Universitetet i Bergen
  • ,
  • Alisa K. Manning, Harvard Medical School, Harvard University
  • ,
  • Anthony Marcketta, Regeneron Pharmaceuticals, Inc.
  • ,
  • Juan Manuel Malacara-Hernandez, University of Chicago, Chicago, Illinois.
  • ,
  • Daniel R. Witte
  • Niels Grarup, Københavns Universitet
  • ,
  • Torben Hansen, Københavns Universitet, Faculty of Health Sciences, University of Southern Denmark, Odense
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  • Oluf Pedersen, Københavns Universitet
  • ,
  • Broad Genomics Platform
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  • DiscovEHR Collaboration
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  • CHARGE
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  • LuCamp
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  • ProDiGY
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  • GoT2D
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  • ESP
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  • SIGMA-T2D
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  • T2D-GENES
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  • AMP-T2D-GENES

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10−3) and candidate genes from knockout mice (P = 5.2 × 10−3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000–185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind570
Nummer7759
Sider (fra-til)71-76
Antal sider6
ISSN0028-0836
DOI
StatusUdgivet - jun. 2019

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