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Nat Genet. 2016 Nov;48(11):1303-1312. doi: 10.1038/ng.3668. Epub 2016 Sep 26.

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
2
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
3
Boston VA Research Institute, Boston, Massachusetts, USA.
4
Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
5
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
7
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
8
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
9
Department of Hematology, University of Cambridge, Cambridge, UK.
10
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
11
Medical Genetics, Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.
12
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
13
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, Netherlands.
14
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
15
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
16
Cardiovascular Medicine Unit, Dep. Medicine, Karolinska Institute, Stockholm, Sweden.
17
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
18
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
19
Vth Department of Medicine, Medical Faculty, Mannheim, Germany.
20
Department of Twin Research & Genetic Epidemiology, King's College London, Londo, UK.
21
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
22
Biology and Genetics, Department Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
23
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
24
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
25
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
26
Renal Unit, Department of Medicine, University of Verona, Verona, Italy.
27
Department of Epidemiology and Biostatistics, Imperial College London, St Mary's campus, London, UK.
28
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Cambridge, UK.
29
University of Cambridge, Cambridge, UK.
30
Division of Nephrology and Dialysis, Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
31
Experimental Genetics Division, Sidra, Doha, Qatar.
32
National Heart and Lung Institute, Imperial College London, London, UK.
33
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
34
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
35
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
36
Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinolgy, Diabetology), Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany.
37
LifeLines Cohort Study, University Medical Center Groningen, Groningen, Netherlands.
38
Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
39
Institute for Systems Genetics, New York University Langone Medical Center, New York, USA.
40
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
41
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
#
Contributed equally

Abstract

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

PMID:
27668658
PMCID:
PMC5279872
DOI:
10.1038/ng.3668
[Indexed for MEDLINE]
Free PMC Article

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