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Am J Hum Genet. 2016 Jul 7;99(1):8-21. doi: 10.1016/j.ajhg.2016.05.007. Epub 2016 Jun 23.

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

Chami N1, Chen MH2, Slater AJ3, Eicher JD2, Evangelou E4, Tajuddin SM5, Love-Gregory L6, Kacprowski T7, Schick UM8, Nomura A9, Giri A10, Lessard S1, Brody JA11, Schurmann C12, Pankratz N13, Yanek LR14, Manichaikul A15, Pazoki R16, Mihailov E17, Hill WD18, Raffield LM19, Burt A20, Bartz TM21, Becker DM14, Becker LC22, Boerwinkle E23, Bork-Jensen J24, Bottinger EP8, O'Donoghue ML25, Crosslin DR26, de Denus S27, Dubé MP1, Elliott P28, Engström G29, Evans MK5, Floyd JS11, Fornage M30, Gao H28, Greinacher A31, Gudnason V32, Hansen T24, Harris TB33, Hayward C34, Hernesniemi J35, Highland HM36, Hirschhorn JN37, Hofman A38, Irvin MR39, Kähönen M40, Lange E41, Launer LJ33, Lehtimäki T42, Li J43, Liewald DC18, Linneberg A44, Liu Y45, Lu Y12, Lyytikäinen LP42, Mägi R17, Mathias RA46, Melander O29, Metspalu A17, Mononen N42, Nalls MA47, Nickerson DA48, Nikus K49, O'Donnell CJ50, Orho-Melander M29, Pedersen O24, Petersmann A51, Polfus L52, Psaty BM53, Raitakari OT54, Raitoharju E42, Richard M30, Rice KM21, Rivadeneira F55, Rotter JI56, Schmidt F57, Smith AV32, Starr JM58, Taylor KD56, Teumer A59, Thuesen BH60, Torstenson ES10, Tracy RP61, Tzoulaki I4, Zakai NA62, Vacchi-Suzzi C63, van Duijn CM16, van Rooij FJ16, Cushman M62, Deary IJ18, Velez Edwards DR64, Vergnaud AC28, Wallentin L65, Waterworth DM66, White HD67, Wilson JG68, Zonderman AB5, Kathiresan S69, Grarup N24, Esko T70, Loos RJ71, Lange LA19, Faraday N72, Abumrad NA6, Edwards TL10, Ganesh SK73, Auer PL74, Johnson AD2, Reiner AP75, Lettre G76.

Author information

1
Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada.
2
Population Sciences Branch, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, MA 01702, USA.
3
Genetics Target Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709, USA; OmicSoft Corporation, Cary, NC 27513, USA.
4
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.
5
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
6
Department of Medicine, Center of Human Nutrition, Washington University School of Medicine, St Louis, MO 63110, USA.
7
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.
8
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10069, USA.
9
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.
10
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA.
11
Department of Medicine, University of Washington, Seattle, WA 98101, USA.
12
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.
13
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
14
Department of Medicine/Division of General Internal Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
15
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
16
Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands.
17
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
18
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
19
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
20
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
21
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
22
Department of Medicine/Divisions of Cardiology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
23
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.
24
The Novo Nordisk Foundation, Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
25
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
26
Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195, USA.
27
Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada.
28
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
29
Department of Clinical Sciences, Malmö, Lund University, Malmö 221 00, Sweden; Skåne University Hospital, Malmö 222 41, Sweden.
30
Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
31
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
32
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
33
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892, USA.
34
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
35
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.
36
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.
37
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
38
Department of Epidemiology, Erasmus, MC Rotterdam 3000, the Netherlands; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
39
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
40
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33014, Finland.
41
Departments of Genetics and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
42
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland.
43
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, School of Medicine, Palo Alto, CA 94305, USA.
44
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.
45
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
46
Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
47
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
48
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
49
University of Tampere, School of Medicine, Tampere 33014, Finland; Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland.
50
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.
51
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
52
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
53
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.
54
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.
55
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.
56
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.
57
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine, Greifswald and Ernst-Mortiz-Arndt University Greifswald, Greifswald 17475, Germany.
58
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Research Centre, Edinburgh EH8 9JZ, UK.
59
Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
60
Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen 2600, Denmark.
61
Departments of Pathology and Laboratory Medicine and Biochemistry, University of Vermont College of Medicine, Colchester, VT 05446, USA.
62
Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
63
Department of Family Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
64
Vanderbilt Epidemiology Center, Department of Obstetrics & Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37203, USA.
65
Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala 751 85, Sweden.
66
Genetics Target Sciences, GlaxoSmithKline, King of Prussia, PA 19406, USA.
67
Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland 1142, New Zealand.
68
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
69
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.
70
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
71
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.
72
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
73
Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48108, USA.
74
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
75
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.
76
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.

Abstract

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.

PMID:
27346685
PMCID:
PMC5005438
DOI:
10.1016/j.ajhg.2016.05.007
[Indexed for MEDLINE]
Free PMC Article

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