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Nat Commun. 2015 Mar 9;6:6065. doi: 10.1038/ncomms7065.

Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.

Author information

1
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
2
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
3
Department of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
4
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam 1081BT, The Netherlands.
5
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
6
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
7
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
8
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands.
9
BioAssist, Netherlands Bioinformatics Center, Nijmegen 6500 HB, The Netherlands.
10
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
11
Department of Biostatistics, Boston U School of Public Health, Boston, Massachusetts 02118, USA.
12
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
13
Department of Biostatistics and Medicine, University of Washington, Seattle, Washington 98101, USA.
14
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
15
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland EH8 9AG, UK.
16
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02176, USA.
17
Department of Psychiatry, VU University Medical Center Amsterdam/GGZinGeest, EMGO+ Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam 1081HL, The Netherlands.
18
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
19
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
20
Department of Genetical Statistics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
21
Division of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
22
Centre for Genomic and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
23
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
24
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
25
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
26
Department of Medicine, University of Washington, Seattle, Washington 98101, USA.
27
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
28
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina NC 27599, USA.
29
Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
30
Department of Medicine and Epidemiology, University of Washington, Seattle, Washington 98101, USA.
31
Department of Genetics and Biostatistics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
32
1] Department of Biostatistics, Boston U School of Public Health, Boston, Massachusetts 02118, USA [2] Framingham Heart Study, Framingham, Massachusetts 01702, USA.
33
Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
34
Department of Human Genetics, Leiden University Medical Center, Leiden P.O. Box 9600, 2300 RC, The Netherlands.
35
1] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
36
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands.
37
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
38
1] Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands [2] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
39
Department of Computer Science, Columbia University, New York, NY 10027-7003, USA.
40
1] Department of Computer Science, Columbia University, New York, NY 10027-7003, USA [2] Department of Systems Biology, Columbia University, New York, NY 10032, USA.
41
Department of Forensic Molecular Biology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
42
Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
43
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, 4103, Germany.
44
Forensic Laboratory for DNA Research, Department of Human Genetics, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
45
Department of Neurology, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
46
Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Medical Center, Amsterdam 1090 GE, The Netherlands.
47
SURFsara, Science Park, Amsterdam 1098 XG, The Netherlands.
48
1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] The Genome Institute, Washington University, St. Louis, MO 98101, USA.
49
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.
50
1] Broad Institute of Harvard and MIT, Cambridge, MA 2142, USA [2] Department of Genetics, Harvard Medical School, Boston, MA 2115, USA.
51
1] Broad Institute of Harvard and MIT, Cambridge, MA 2142, USA [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 2115, USA.
52
Department of Genome Sciences, University of Washington, Seattle, WA 98101, USA.
53
Centrum voor Wiskunde en Informatica, Life Sciences Group, Amsterdam 1098 XG, The Netherlands.
54
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands.
55
Department of Endocrinology, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
56
Rinat-Pfizer Inc, South San Francisco, CA 10017, USA.
57
BGI-Shenzhen, Shenzhen 518083, China.
58
BGI-Europe, Copenhagen DK-1870, Denmark.
59
1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark [3] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2100, Denmark.
60
Legal Pathways Institute for Health and Bio Law, Aerdenhout, The Netherlands.

Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

PMID:
25751400
PMCID:
PMC4366498
DOI:
10.1038/ncomms7065
[Indexed for MEDLINE]
Free PMC Article

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