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J Med Genet. 2016 Jul;53(7):441-9. doi: 10.1136/jmedgenet-2015-103439. Epub 2016 Apr 1.

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.

Author information

1
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
2
Human Genome Sequencing Center, Baylor College of Medicine, Houston, USA.
3
Department of Medicine, University of Washington, Seattle, USA.
4
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK The Framingham Heart Study, NHLBI Cardiovascular Epidemiology and Human Genomics Branch, Framingham, USA.
5
Center for Public Health Genomics, University of Virginia, Charlottesville, USA.
6
Icelandic Heart Association, Kopavogur, Iceland Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
7
Department of Genetics, Washington University School of Medicine, St Louis, USA.
8
Department of Biostatistics, Boston University School of Public Health, Boston, USA.
9
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
10
Department of Genetics, University of North Carolina, Chapel Hill, USA.
11
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
12
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
13
Human Genomics Unit, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
14
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
15
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK.
16
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam, The Netherlands.
17
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
18
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
19
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
20
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
21
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
22
Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, USA.
23
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
24
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
25
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
26
Human Genetics Center, The University of Texas School of Public Health, Houston, USA.
27
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
28
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
29
Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
30
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.
31
British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
32
Department of Biostatistics, University of Washington, Seattle, USA.
33
Brigham and Women's Hospital, Boston, USA.
34
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, USA.
35
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
36
Faculty of Medicine, University of Split, Split, Croatia.
37
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
38
Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.
39
Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK Imperial College Healthcare NHS Trus, Imperial College London, London, UK.
40
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
41
Department of Psychiatry, VU University Medical Center Amsterdam/GGZinGeest and EMGO+ Institute for Health and Care Research and Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
42
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
43
Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
44
Department of Clinical Physiology, Turku University Hospital, Turku, Finland Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
45
Division of Medicine, Turku University Hospital, Turku, Finland Department of Medicine, University of Turku, Turku, Finland.
46
Department of Cardiology, Heart Hospital, Tampere University Hospital, Tampere, Finland School of Medicine, University of Tampere, Tampere, Finland.
47
Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Jamaica.
48
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
49
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
50
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
51
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
52
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
53
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
54
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
55
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands Epidemiology Section, Department of BESC, King Faisal Medical Hospital and Research Centre, Riyadh, Saudi Arabia.
56
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK Imperial College Healthcare NHS Trus, Imperial College London, London, UK.
57
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
58
Human Genomics Unit, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland Public Health, University of Helsinki, Helsinki, Finland Wellcome Trust Sanger Institute, UK.
59
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
60
Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA.
61
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
62
Department of Medicine, University of Washington, Seattle, USA Department of Epidemiology, University of Washington, Seattle, USA Department of Health Services, University of Washington, Seattle, USA Group Health Cooperative, Group Health Research Institute, Seattle, USA.
63
Human Genome Sequencing Center, Baylor College of Medicine, Houston, USA Human Genetics Center, The University of Texas School of Public Health, Houston, USA.
64
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, USA Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, USA Departments of Pediatrics, Medicine, and Human Genetics, UCLA, Los Angeles, USA.
65
The Framingham Heart Study, NHLBI Cardiovascular Epidemiology and Human Genomics Branch, Framingham, USA Department of Genetics, Washington University School of Medicine, St Louis, USA.

Abstract

BACKGROUND:

So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS:

We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS:

Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS:

This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

KEYWORDS:

Complex traits; Epidemiology; Genetics; Genome-wide; circulating lipid levels

PMID:
27036123
PMCID:
PMC4941146
DOI:
10.1136/jmedgenet-2015-103439
[Indexed for MEDLINE]
Free PMC Article

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