Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Autor:	Chami N; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada., Chen MH; Population Sciences Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA., Slater AJ; Genetics Target Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA; OmicSoft Corporation, Cary, NC 27513, USA., Eicher JD; Population Sciences Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA., Evangelou E; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece., Tajuddin SM; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA., Love-Gregory L; Department of Medicine, Center of Human Nutrition, Washington University School of Medicine, St Louis, MO 63110, USA., Kacprowski T; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine, Greifswald and Ernst-Mortiz-Arndt University Greifswald, Greifswald 17475, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald QA, Germany., Schick UM; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA., Nomura A; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medical Science, Kanazawa, Ishikawa 9200942, Japan., Giri A; Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA., Lessard S; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada., Brody JA; Department of Medicine, University of Washington, Seattle, WA 98101, USA., Schurmann C; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA., Pankratz N; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA., Yanek LR; Department of Medicine/Division of General Internal Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA., Manichaikul A; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA., Pazoki R; Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands., Mihailov E; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia., Hill WD; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK., Raffield LM; Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA., Burt A; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA., Bartz TM; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA., Becker DM; Department of Medicine/Division of General Internal Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA., Becker LC; Department of Medicine/Divisions of Cardiology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Boerwinkle E; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Bork-Jensen J; The Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark., Bottinger EP; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA., O'Donoghue ML; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA., Crosslin DR; Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA., de Denus S; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada., Dubé MP; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada., Elliott P; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK., Engström G; Department of Clinical Sciences, Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden., Evans MK; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA., Floyd JS; Department of Medicine, University of Washington, Seattle, WA 98101, USA., Fornage M; Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Gao H; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK., Greinacher A; Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany., Gudnason V; Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland., Hansen T; The Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark., Harris TB; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892, USA., Hayward C; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK., Hernesniemi J; Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland; University of Tampere, School of Medicine, Tampere 33014, Finland., Highland HM; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Hirschhorn JN; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA., Hofman A; Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA., Irvin MR; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Kähönen M; Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33014, Finland., Lange E; Departments of Genetics and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Launer LJ; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892, USA., Lehtimäki T; Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland., Li J; Department of Medicine, Division of Cardiovascular Medicine, Stanford University, School of Medicine, Palo Alto, CA 94305, USA., Liewald DC; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK., Linneberg A; Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen 2600, Denmark; Department of Clinical Experimental Research, Rigshospitalet, Glostrup 2100, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark., Liu Y; Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA., Lu Y; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA., Lyytikäinen LP; Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland., Mägi R; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia., Mathias RA; Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Melander O; Department of Clinical Sciences, Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden., Metspalu A; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia., Mononen N; Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland., Nalls MA; Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA., Nikus K; University of Tampere, School of Medicine, Tampere 33014, Finland; Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland., O'Donnell CJ; Population Sciences Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA; Cardiology Section and Center for Population Genomics, Boston Veteran's Administration (VA) Healthcare, Boston, MA 02118, USA., Orho-Melander M; Department of Clinical Sciences, Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden., Pedersen O; The Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark., Petersmann A; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany., Polfus L; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA., Raitakari OT; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland., Raitoharju E; Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland., Richard M; Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Rice KM; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA., Rivadeneira F; Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam 3000, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam 3015, the Netherlands., Rotter JI; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA., Schmidt F; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine, Greifswald and Ernst-Mortiz-Arndt University Greifswald, Greifswald 17475, Germany., Smith AV; Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland., Starr JM; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Research Centre, Edinburgh EH8 9JZ, UK., Taylor KD; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA., Teumer A; Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany., Thuesen BH; Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen 2600, Denmark., Torstenson ES; Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA., Tracy RP; Departments of Pathology and Laboratory Medicine and Biochemistry, University of Vermont College of Medicine, Colchester, VT 05446, USA., Tzoulaki I; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece., Zakai NA; Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA., Vacchi-Suzzi C; Department of Family Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA., van Duijn CM; Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands., van Rooij FJ; Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands., Cushman M; Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA., Deary IJ; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK., Velez Edwards DR; Vanderbilt Epidemiology Center, Department of Obstetrics & Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA., Vergnaud AC; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK., Wallentin L; Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala 751 85, Sweden., Waterworth DM; Genetics Target Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA., White HD; Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland 1142, New Zealand., Wilson JG; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA., Zonderman AB; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA., Kathiresan S; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Grarup N; The Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark., Esko T; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia., Loos RJ; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA; The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA., Lange LA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA., Faraday N; Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Abumrad NA; Department of Medicine, Center of Human Nutrition, Washington University School of Medicine, St Louis, MO 63110, USA., Edwards TL; Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA., Ganesh SK; Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA., Auer PL; Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA., Johnson AD; Population Sciences Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA., Reiner AP; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: apreiner@u.washington.edu., Lettre G; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada. Electronic address: guillaume.lettre@umontreal.ca.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2016 Jul 07; Vol. 99 (1), pp. 8-21. Date of Electronic Publication: 2016 Jun 23.
DOI:	10.1016/j.ajhg.2016.05.007
Abstrakt:	Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated. (Copyright © 2016 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
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