Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.
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.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Valentina
V
Iotchkova
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Boston VA Research Institute, Boston, Massachusetts, USA.
Jie
J
Huang
Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Québec, Canada.|Department of Human Genetics, McGill University, Montréal, Québec, Canada.
John A
JA
Morris
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Deepti
D
Jain
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Caterina
C
Barbieri
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Klaudia
K
Walter
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Josine L
JL
Min
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Department of Hematology, University of Cambridge, Cambridge, UK.
Lu
L
Chen
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
William
W
Astle
Medical Genetics, Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
Massimilian
M
Cocca
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
Patrick
P
Deelen
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Heather
H
Elding
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
Aliki-Eleni
AE
Farmaki
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Christopher S
CS
Franklin
Cardiovascular Medicine Unit, Dep. Medicine, Karolinska Institute, Stockholm, Sweden.
Mattias
M
Franberg
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Tom R
TR
Gaunt
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Albert
A
Hofman
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Tao
T
Jiang
Vth Department of Medicine, Medical Faculty, Mannheim, Germany.
Marcus E
ME
Kleber
Department of Twin Research & Genetic Epidemiology, King's College London, Londo, UK.
Genevieve
G
Lachance
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Jian'an
J
Luan
Biology and Genetics, Department Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
Giovanni
G
Malerba
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Angela
A
Matchan
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Daniel
D
Mead
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Yasin
Y
Memari
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
Ioanna
I
Ntalla
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Kalliope
K
Panoutsopoulou
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Raha
R
Pazoki
Department of Twin Research & Genetic Epidemiology, King's College London, Londo, UK.|MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
John R B
JRB
Perry
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.|Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
Fernando
F
Rivadeneira
Cardiovascular Medicine Unit, Dep. Medicine, Karolinska Institute, Stockholm, Sweden.
Maria
M
Sabater-Lleal
Cardiovascular Medicine Unit, Dep. Medicine, Karolinska Institute, Stockholm, Sweden.
Bengt
B
Sennblad
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
So-Youn
SY
Shin
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
Lorraine
L
Southam
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Michela
M
Traglia
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
Freerk
F
van Dijk
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Elisabeth M
EM
van Leeuwen
Renal Unit, Department of Medicine, University of Verona, Verona, Italy.
Gianluigi
G
Zaza
Department of Epidemiology and Biostatistics, Imperial College London, St Mary's campus, London, UK.
Weihua
W
Zhang
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Najaf
N
Amin
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|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.
Adam
A
Butterworth
Department of Epidemiology and Biostatistics, Imperial College London, St Mary's campus, London, UK.
John C
JC
Chambers
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
George
G
Dedoussis
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Abbas
A
Dehghan
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Oscar H
OH
Franco
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.
Lude
L
Franke
University of Cambridge, Cambridge, UK.
Mattia
M
Frontini
Division of Nephrology and Dialysis, Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
Giovanni
G
Gambaro
Medical Genetics, Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.|Experimental Genetics Division, Sidra, Doha, Qatar.
Paolo
P
Gasparini
Cardiovascular Medicine Unit, Dep. Medicine, Karolinska Institute, Stockholm, Sweden.
Anders
A
Hamsten
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Aaron
A
Issacs
National Heart and Lung Institute, Imperial College London, London, UK.
Jaspal S
JS
Kooner
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Charles
C
Kooperberg
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Claudia
C
Langenberg
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.|Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.|Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinolgy, Diabetology), Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany.
Winfried
W
Marz
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Robert A
RA
Scott
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.|LifeLines Cohort Study, University Medical Center Groningen, Groningen, Netherlands.
Morris A
MA
Swertz
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Daniela
D
Toniolo
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
Andre G
AG
Uitterlinden
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
Cornelia M
CM
van Duijn
Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
Hugh
H
Watkins
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Eleftheria
E
Zeggini
Institute for Systems Genetics, New York University Langone Medical Center, New York, USA.
Mathew T
MT
Maurano
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Nicholas J
NJ
Timpson
Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Alexander P
AP
Reiner
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
Paul L
PL
Auer
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Department of Hematology, University of Cambridge, Cambridge, UK.|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.
Nicole
N
Soranzo
D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006331:Heart Diseases / Q000235:genetics*; D006402:Hematologic Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA
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