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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Flannick, Jason; Mercader, Josep M; Fuchsberger, Christian; Udler, Miriam S; Mahajan, Anubha; Wessel, Jennifer; Teslovich, Tanya M; Caulkins, Lizz; Koesterer, Ryan; Barajas-Olmos, Francisco; Blackwell, Thomas W; Boerwinkle, Eric; Brody, Jennifer A; Centeno-Cruz, Federico; Chen, Ling; Chen, Siying; Contreras-Cubas, Cecilia; Córdova, Emilio; Correa, Adolfo; Cortes, Maria; DeFronzo, Ralph A; Dolan, Lawrence; Drews, Kimberly L; Elliott, Amanda; Floyd, James S; Gabriel, Stacey; Garay-Sevilla, Maria Eugenia; García-Ortiz, Humberto; Gross, Myron; Han, Sohee; Heard-Costa, Nancy L; Jackson, Anne U; Jørgensen, Marit E; Kang, Hyun Min; Kelsey, Megan; Kim, Bong-Jo; Koistinen, Heikki A; Kuusisto, Johanna; Leader, Joseph B; Linneberg, Allan; Liu, Ching-Ti; Liu, Jianjun; Lyssenko, Valeriya; Manning, Alisa K; Marcketta, Anthony; Malacara-Hernandez, Juan Manuel; Martínez-Hernández, Angélica; Matsuo, Karen; Mayer-Davis, Elizabeth; Mendoza-Caamal, Elvia.
Afiliación
  • Flannick J; Program in Metabolism, Broad Institute, Cambridge, MA, USA. flannick@broadinstitute.org.
  • Mercader JM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. flannick@broadinstitute.org.
  • Fuchsberger C; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. flannick@broadinstitute.org.
  • Udler MS; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA. flannick@broadinstitute.org.
  • Mahajan A; Program in Metabolism, Broad Institute, Cambridge, MA, USA.
  • Wessel J; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
  • Teslovich TM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Caulkins L; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
  • Koesterer R; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Barajas-Olmos F; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Blackwell TW; Institute for Biomedicine, Eurac Research, Bolzano, Italy.
  • Boerwinkle E; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Brody JA; Program in Metabolism, Broad Institute, Cambridge, MA, USA.
  • Centeno-Cruz F; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
  • Chen L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Chen S; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
  • Contreras-Cubas C; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Córdova E; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Correa A; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Cortes M; Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
  • DeFronzo RA; Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA.
  • Dolan L; Diabetes Translational Research Center, Indiana University, Indianapolis, IN, USA.
  • Drews KL; Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
  • Elliott A; Program in Metabolism, Broad Institute, Cambridge, MA, USA.
  • Floyd JS; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
  • Gabriel S; Program in Metabolism, Broad Institute, Cambridge, MA, USA.
  • Garay-Sevilla ME; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
  • García-Ortiz H; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Gross M; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Han S; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Heard-Costa NL; 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.
  • Jackson AU; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
  • Jørgensen ME; Cardiovascular Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Kang HM; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Kelsey M; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
  • Kim BJ; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Koistinen HA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Kuusisto J; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Leader JB; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Linneberg A; Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
  • Liu CT; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
  • Liu J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lyssenko V; Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
  • Manning AK; Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Marcketta A; Biostatistics Center, George Washington University, Rockville, MD, USA.
  • Malacara-Hernandez JM; Program in Metabolism, Broad Institute, Cambridge, MA, USA.
  • Martínez-Hernández A; Program in Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
  • Matsuo K; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
  • Mayer-Davis E; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Mendoza-Caamal E; Department of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
Nature ; 570(7759): 71-76, 2019 06.
Article en En | MEDLINE | ID: mdl-31118516
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 1_ASSA2030 Problema de salud: 1_doencas_nao_transmissiveis Asunto principal: Diabetes Mellitus Tipo 2 / Exoma / Secuenciación del Exoma Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 1_ASSA2030 Problema de salud: 1_doencas_nao_transmissiveis Asunto principal: Diabetes Mellitus Tipo 2 / Exoma / Secuenciación del Exoma Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
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