Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.

Autor: Wheeler MM; Department of Genome Sciences, University of Washington, Seattle, WA, 98105, USA., Stilp AM; Department of Biostatistics, University of Washington, Seattle, WA, 98105, USA., Rao S; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, Boston, MA, 02138, USA.; Broad Institute, Cambridge, MA, 02142, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China., Halldórsson BV; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Technology, Reykjavik University, Reykjavík, Iceland., Beyter D; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Wen J; Departments of Biostatistics, Genetics, Computer Science, Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Mihkaylova AV; Department of Biostatistics, University of Washington, Seattle, WA, 98105, USA., McHugh CP; Department of Biostatistics, University of Washington, Seattle, WA, 98105, USA., Lane J; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA., Jiang MZ; Departments of Biostatistics, Genetics, Computer Science, Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Raffield LM; Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA., Jun G; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Sedlazeck FJ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Metcalf G; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Yao Y; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, Boston, MA, 02138, USA.; Broad Institute, Cambridge, MA, 02142, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA., Bis JB; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA., Chami N; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., de Vries PS; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.; Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Desai P; Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, 10065, USA., Floyd JS; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA., Gao Y; Jackson Heart Study, Department of Medicine, University of Mississippi, Jackson, MS, 39216, USA., Kammers K; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA., Kim W; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 2115, USA., Moon JY; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA., Ratan A; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA., Yanek LR; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA., Almasy L; Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA., Becker LC; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA., Blangero J; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA., Cho MH; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 2115, USA., Curran JE; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA., Fornage M; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Kaplan RC; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA., Lewis JP; Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA., Loos RJF; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Mitchell BD; Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA., Morrison AC; Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Preuss M; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA., Tang H; Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA., Tracy RP; Departments of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, 5446, USA., Boerwinkle E; Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Abecasis GR; TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI, 48109, USA., Blackwell TW; TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI, 48109, USA., Smith AV; TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI, 48109, USA., Johnson AD; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, 1702, USA., Mathias RA; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA, 98105, USA., Conomos MP; Department of Biostatistics, University of Washington, Seattle, WA, 98105, USA., Li Y; Departments of Biostatistics, Genetics, Computer Science, Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Þorsteinsdóttir U; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Magnússon MK; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Stefansson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland., Pankratz ND; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA., Bauer DE; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, Boston, MA, 02138, USA.; Broad Institute, Cambridge, MA, 02142, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA., Auer PL; Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. pauer@mcw.edu., Reiner AP; Department of Epidemiology, University of Washington, Seattle, WA, 98105, USA. apreiner@uw.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Dec 08; Vol. 13 (1), pp. 7592. Date of Electronic Publication: 2022 Dec 08.
DOI: 10.1038/s41467-022-35354-7
Abstrakt: Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
(© 2022. The Author(s).)
Databáze: MEDLINE
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