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PLoS One. 2017 Jan 20;12(1):e0167742. doi: 10.1371/journal.pone.0167742. eCollection 2017.

Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.

Author information

1
Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
2
University of Texas Health Science Center at Houston, Houston, TX, United States of America.
3
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
4
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, United States of America.
5
Harvard Medical School, Boston, MA, United States of America.
6
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
7
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
8
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
9
Novo Nordisk Foundation Center For Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
11
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
12
Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
13
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, United States of America.
14
Centre for Vision Research, Department of Ophthalmology, and Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
15
Public Health Stream, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
16
School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
17
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
18
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.
19
Queensland Brain Institute, University of Queensland, Brisbane, Australia.
20
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.
21
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States of America.
22
Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, the Netherlands.
23
EMGO+ institute, VU University & VU medical center, Amsterdam, the Netherlands.
24
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
25
Department of Medicine, University of Washington, Seattle WA, United States of America.
26
Division of Infection and Immunology, UCL, London, United Kingdom.
27
Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
28
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States of America.
29
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
30
Division of Biostatistics, University of Minnesota, Minneapolis, MN, United States of America.
31
Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
32
Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.
33
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
34
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
35
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor/UCLA Medical Center, Torrance, CA, United States of America.
36
Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States of America.
37
Royal College of Surgeons in Ireland, Department of Psychiatry, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
38
University College Dublin, UCD Conway Institute, Centre for Proteome Research, UCD, Belfield, Dublin, Ireland.
39
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
40
NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, United Kingdom.
41
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
42
Royal North Shore Hospital, Sydney University, Sydney, Australia.
43
Department of Hematology, Erasmus MC, Rotterdam, the Netherlands.
44
Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
45
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom.
46
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
47
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
48
Department of Biostatistics, University of Washington, Seattle, WA, United States of America.
49
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
50
Public Health Stream, Hunter Medical Research Institute, and School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
51
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
52
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States of America.
53
Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
54
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
55
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
56
Department of General and Interventional Cardiology, University Heart Centre, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
57
German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Lübeck, Kiel, Hamburg, Germany.
58
Department of Medicine, Epidemiology, and Health Services, University of Washington, Seattle WA, United States of America.
59
Group Health Research Institute, Group Health Cooperative, Seattle WA, United States of America.
60
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
61
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MS, United States of America.
62
Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Institute for Translational Genomics and Population Sciences, Torrance, CA, United States of America.
63
Division of Genomic Outcomes, Departments of Pediatrics & Medicine, Harbor-UCLA Medical Center, Torrance, CA, United States of America.
64
Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
65
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
66
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
67
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
68
Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
69
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
70
German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany.
71
Cardiovascular Medicine Dept/Radcliffe Dept of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
72
Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands.
73
Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
74
Information based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
75
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
76
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
77
Cardiology Division, Massachusetts General Hospital, Boston, MA, United States of America.
78
Department of Epidemiology, University of Washington, Seattle WA, United States of America.
79
Seattle Epidemiologic Research and Information Center, Department of Veteran Affairs Office of Research and Development, Seattle, WA, United States of America.
80
Population Health Research Institute, St George's, University of London, London, United Kingdom.
81
Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.

Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

PMID:
28107422
PMCID:
PMC5249120
DOI:
10.1371/journal.pone.0167742
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Dr. BM Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Steno Diabetes Center and Synlab Holding Deutschland GmbH provided support in the form of salaries for authors T.S.A. and W.M. respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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