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Am J Hum Genet. 2016 Jul 7;99(1):22-39. doi: 10.1016/j.ajhg.2016.05.003. Epub 2016 Jun 23.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

Author information

1
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
2
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Population Sciences Branch, National Heart Lung and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA.
4
Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada.
5
Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 37235, USA.
6
Department of Medicine, University of Washington, Seattle, WA 98101, USA.
7
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
8
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, Germany.
9
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
10
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland.
11
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
12
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
13
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
14
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
15
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands.
16
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
17
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
18
Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
19
Genetics, Target Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA.
20
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.
21
Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
22
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
23
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
24
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892, USA.
25
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.
26
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
27
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
28
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
29
Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
30
Department of Genome Sciences, School of Medicine, University of Washington, Seattle, WA 98105, USA.
31
Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland; University of Tampere School of Medicine, Tampere 33014, Finland.
32
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, Edinburgh EH8 9JZ, UK.
33
Vanderbilt Epidemiology Center, Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA.
34
Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, 751 85 Uppsala, Sweden.
35
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
36
Department of Medicine, Divisions of Cardiology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
37
Department of Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, TN 37203, USA.
38
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 13347, Germany.
39
Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
40
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
41
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
42
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam 3015, the Netherlands.
43
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.
44
Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada.
45
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
46
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
47
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000, the Netherlands; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
48
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald and Ernst-Mortiz-Arndt University Greifswald, Greifswald 17475, Germany.
49
Departments of Genetics and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
50
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.
51
Morehouse School of Medicine, Social Epidemiology Research Center, Cardiovascular Research Institute, Atlanta, GA 30310, USA.
52
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.
53
Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.
54
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; Department of Cardiology, University Medicine Greifswald, Greifswald 17475, Germany.
55
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33014, Finland.
56
Cardiovascular Health Research Unit, Departments of Epidemiology, Health Services, and Medicine, University of Washington, Seattle, WA 98101, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
57
OmicSoft Corporation, Cary, NC 27513, USA; Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
58
Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland 1142, New Zealand.
59
Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA.
60
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
61
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
62
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
63
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
64
Division of Hematology Oncology, Department of Medicine, The University of Vermont, Colchester, VT 05446, USA.
65
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA.
66
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.
67
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA. Electronic address: pauer@uwm.edu.

Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

PMID:
27346689
PMCID:
PMC5005433
DOI:
10.1016/j.ajhg.2016.05.003
[Indexed for MEDLINE]
Free PMC Article

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