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在97,691个全基因组中遗传性血液形成的原因

Alexander G Bick ^1,2,3,4, Joshua S Weinstock ⁵, Satish K Nandakumar ^2,6

¹Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³Harvard Medical School, Boston, MA, USA.
⁴Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁸Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
⁹Yale School of Medicine, New Haven, CT, USA.
¹⁰Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹²Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁴Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁵Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁸Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁹Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
²⁰Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
²¹Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²²Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²³Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁴Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁵Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁶Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁷Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁸Department of Health Services, University of Washington, Seattle, WA, USA.
²⁹Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁰Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³¹Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³²Departments of Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.
³³Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³⁴Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA.
³⁵Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
³⁶Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³⁷Tulane University Translational Science Institute, New Orleans, LA, USA.
³⁸Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
³⁹Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
⁴⁰Seattle Epidemiologic Information and Research Center, Department of Veterans Affairs, Office of Research and Development, Seattle, WA, USA.
⁴¹College of Public Health, University of Kentucky, Lexington, KY, USA.
⁴²Department of Medicine, University of Colorado, Aurora, CO, USA.
⁴³Departments of Medicine and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁴Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴⁵Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴⁶Bloodworks Northwest, Seattle, WA, USA.
⁴⁷Department of Medicine, University of Washington, Seattle, WA, USA.
⁴⁸Vitalant Research Institute, San Francisco, CA, USA.
⁴⁹Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵⁰Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
⁵¹Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵²Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
⁵³Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁵⁴Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA.
⁵⁵Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁵⁸Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
⁵⁹Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁶⁰Departments of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁶¹GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁶²Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁶³Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁴Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁵Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
⁶⁶Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁸Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁹Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
⁷⁰Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁷¹Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁷²Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷³Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁷⁴Department of Preventive Medicine, Northwestern Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷⁵Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷⁶Framingham Heart Study, Framingham, MA, USA.
⁷⁷Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷⁸Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
⁷⁹Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
⁸⁰Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁸¹Center for Genes Environment and Health, National Jewish Health, Denver, CO, USA.
⁸²Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁸³Department of Genome Science, University of Washington, Seattle, WA, USA.
⁸⁴Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁸⁵Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸⁶Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁸⁷Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁸Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁹Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹⁰Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁹¹Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹²Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
⁹³Department of Medicine, Weill Cornell Medical School, New York, NY, USA.
⁹⁴Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁵Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁶Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
⁹⁷Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁸Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA.
⁹⁹Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
¹⁰⁰Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰¹Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁰²Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰³Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁴Department of Biology, MIT, Cambridge, MA, USA.
¹⁰⁵Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
¹⁰⁶Howard Hughes Medical Institute, Boston, MA, USA.
¹⁰⁷Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰⁸Regeneron Pharmaceuticals, Tarrytown, NY, USA.
¹⁰⁹Broad Institute of MIT and Harvard, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹⁰Harvard Medical School, Boston, MA, USA. sekar@broadinstitute.org.
¹¹¹Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. sekar@broadinstitute.org.
¹¹²Verve Therapeutics, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹³Broad Institute of MIT and Harvard, Cambridge, MA, USA. pradeep@broadinstitute.org.
¹¹⁴Harvard Medical School, Boston, MA, USA. pradeep@broadinstitute.org.
¹¹⁵Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. pradeep@broadinstitute.org.

⁰Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Nature +

|

2020年十月15日

在PubMed上查看摘要

概括

年龄增长会增加慢性疾病的风险. 这项研究确定了影响克隆性血液形成 (CHIP) 的遗传因素,这是一种与癌症和心脏病相关的疾病,揭示了生殖系变异如何影响干细胞功能.

科学领域

基因组学
血液学
老龄化研究

背景情况

年龄是慢性疾病的主要危险因素,
不确定潜力的克隆性血液形成 (CHIP),其特征是血液形成干细胞的与年龄相关的体质突变,与血液癌症和冠状动脉疾病有关.
了解CHIP的遗传基础对于阐明与衰老相关的疾病风险至关重要.

研究的目的

在CHIP的发展中研究生殖基因和体质突变之间的相互作用.
确定与CHIP状态及其驱动基因相关的遗传变异和基因位点.
探索生殖系遗传变异对造血干细胞 (HSC) 功能和CHIP病变的功能影响.

主要方法

分析了TOPMed计划中97,691名不同参与者的高覆盖全基因组序列.
鉴定CHIP个体和血液细胞,脂质和炎症特征的关联分析.
全基因组关联研究 (GWAS) 以确定与CHIP相关的生殖系遗传变异,随后对包括TET2基因在内的已识别的基因位置进行in silico和in vitro评估.

主要成果

发现了4,229名CHIP患者.
在CHIP驱动基因和血液细胞,脂质和炎症特征之间发现了特定的关联.
确定了与CHIP身份相关的三个遗传位点,其中包括特定于非洲血统的个体的TET2位点.
鉴定出一种干扰TET2远端增强剂的致病性生殖系变体,导致HSC自我更新的增加.

结论

生殖系遗传变异显著影响HSC功能,并为CHIP的发展做出贡献.
CHIP是通过特定于克隆造血的机制产生的,并且与组织间的体质突变共享.
这项研究提供了与衰老相关疾病的遗传基础,并强调了生殖基因在CHIP中的作用.

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