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Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Bick, Alexander G; Weinstock, Joshua S; Nandakumar, Satish K; Fulco, Charles P; Bao, Erik L; Zekavat, Seyedeh M; Szeto, Mindy D; Liao, Xiaotian; Leventhal, Matthew J; Nasser, Joseph; Chang, Kyle; Laurie, Cecelia; Burugula, Bala Bharathi; Gibson, Christopher J; Lin, Amy E; Taub, Margaret A; Aguet, Francois; Ardlie, Kristin; Mitchell, Braxton D; Barnes, Kathleen C; Moscati, Arden; Fornage, Myriam; Redline, Susan; Psaty, Bruce M; Silverman, Edwin K; Weiss, Scott T; Palmer, Nicholette D; Vasan, Ramachandran S; Burchard, Esteban G; Kardia, Sharon L R; He, Jiang; Kaplan, Robert C; Smith, Nicholas L; Arnett, Donna K; Schwartz, David A; Correa, Adolfo; de Andrade, Mariza; Guo, Xiuqing; Konkle, Barbara A; Custer, Brian; Peralta, Juan M; Gui, Hongsheng; Meyers, Deborah A; McGarvey, Stephen T; Chen, Ida Yii-Der; Shoemaker, M Benjamin; Peyser, Patricia A; Broome, Jai G; Gogarten, Stephanie M; Wang, Fei Fei.
Afiliación
  • Bick AG; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Weinstock JS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Nandakumar SK; Harvard Medical School, Boston, MA, USA.
  • Fulco CP; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Bao EL; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Zekavat SM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Szeto MD; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Liao X; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Leventhal MJ; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • Nasser J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chang K; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Laurie C; Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
  • Burugula BB; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gibson CJ; Yale School of Medicine, New Haven, CT, USA.
  • Lin AE; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Taub MA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Aguet F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ardlie K; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Mitchell BD; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Barnes KC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Moscati A; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Fornage M; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Redline S; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Psaty BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Silverman EK; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Weiss ST; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Palmer ND; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Vasan RS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Burchard EG; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Kardia SLR; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
  • He J; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Kaplan RC; Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
  • Smith NL; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Arnett DK; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Schwartz DA; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Correa A; Harvard Medical School, Boston, MA, USA.
  • de Andrade M; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Guo X; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Konkle BA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Custer B; Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Peralta JM; Department of Health Services, University of Washington, Seattle, WA, USA.
  • Gui H; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
  • Meyers DA; Harvard Medical School, Boston, MA, USA.
  • McGarvey ST; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Chen IY; Harvard Medical School, Boston, MA, USA.
  • Shoemaker MB; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Peyser PA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Broome JG; Departments of Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.
  • Gogarten SM; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Wang FF; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA.
Nature ; 586(7831): 763-768, 2020 10.
Article en En | MEDLINE | ID: mdl-33057201
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Genoma Humano / Predisposición Genética a la Enfermedad / Secuenciación Completa del Genoma / Hematopoyesis Clonal Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged País/Región como asunto: Africa / America do norte Idioma: En Revista: Nature Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Genoma Humano / Predisposición Genética a la Enfermedad / Secuenciación Completa del Genoma / Hematopoyesis Clonal Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged País/Región como asunto: Africa / America do norte Idioma: En Revista: Nature Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos