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Am J Hum Genet. 2017 Jan 5;100(1):51-63. doi: 10.1016/j.ajhg.2016.11.016. Epub 2016 Dec 22.

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Author information

1
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
2
GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Icelandic Heart Association, 210 Kopavogur, Iceland.
4
Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Pediatric Hematology/Oncology at DFCI, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
5
Department of Cardiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
6
National Institute on Aging, NIH, Baltimore, MD 21224, USA.
7
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
8
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
9
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
10
Division of Cardiovascular Medicine, Department of Internal Medicine, Department of Human Genetics, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
11
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
12
Icahn Institute for Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
13
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
14
Department of General and Interventional Cardiology, University Heart Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Lübeck, Kiel, Hamburg 20246, Germany.
15
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
16
Department of Medicine, University of Washington, Seattle, WA 98195-6420, USA.
17
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, 91375-345 Mashhad, Iran.
18
National Institute on Aging, NIH, Bethesda, MD 20892-9205, USA.
19
Department of Cardiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
20
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
21
University of Michigan Medical School, Ann Arbor, MI 48109, USA.
22
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
23
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
24
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8010 Graz, Austria.
25
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
26
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
27
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
28
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, 55131 Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
29
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
30
Robertson Center for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
31
Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
32
Quantitative Sciences Unit, School of Medicine, Stanford University, Stanford, CA 94304, USA.
33
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
34
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
35
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
36
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, 8010 Graz, Austria; Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, 8010 Graz, Austria.
37
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
38
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
39
Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.
40
Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
41
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
42
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
43
Cardiovascular Medicine Division, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA.
44
Icelandic Heart Association, 210 Kopavogur, Iceland.
45
Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
46
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, 55131 Mainz, Germany.
47
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
48
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
49
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, NIH, Bethesda, MD 20892-9205, USA.
50
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
51
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300 AC, the Netherlands.
52
Health Disparities Research Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, MD 20892, USA.
53
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Pediatric Hematology/Oncology at DFCI, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA; Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
54
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
55
Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
56
Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 03722, Korea.
57
Johns Hopkins Bloomberg School of Public Health, George W. Comstock Center for Public Health Research and Prevention, Comstock Center & Cardiovascular Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, MD 21205, USA.
58
School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
59
Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD 21225, USA.
60
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA; Department of Biostatistics, Boston University of Public Health, Boston, MA 02118, USA.
61
Departments of Epidemiology, Health Services, and Medicine, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
62
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300 AC, the Netherlands; Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Department of Public Health and Primary Care, Leiden University Medical Center, 2300 AC Leiden, the Netherlands.
63
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
64
Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College, W2 1PG London, UK.
65
Department of Biostatistics, University of Liverpool, Block F, Waterhouse Building, 1-5 Brownlow Street, Liverpool L69 3GL, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
66
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
67
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
68
Division of Cardiovascular Medicine, Department of Internal Medicine, Department of Human Genetics, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: sganesh@umich.edu.

Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

PMID:
28017375
PMCID:
PMC5223059
DOI:
10.1016/j.ajhg.2016.11.016
[Indexed for MEDLINE]
Free PMC Article

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