Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.
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.
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Elisabeth M
EM
van Leeuwen
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Lennart C
LC
Karssen
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Joris
J
Deelen
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Aaron
A
Isaacs
Department of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Carolina
C
Medina-Gomez
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam 1081BT, The Netherlands.
Hamdi
H
Mbarek
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
Alexandros
A
Kanterakis
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Stella
S
Trompet
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Iris
I
Postmus
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands.
Niek
N
Verweij
BioAssist, Netherlands Bioinformatics Center, Nijmegen 6500 HB, The Netherlands.
David J
DJ
van Enckevort
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
Jennifer E
JE
Huffman
Department of Biostatistics, Boston U School of Public Health, Boston, Massachusetts 02118, USA.
Charles C
CC
White
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Mary F
MF
Feitosa
Department of Biostatistics and Medicine, University of Washington, Seattle, Washington 98101, USA.
Traci M
TM
Bartz
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
Ani
A
Manichaikul
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland EH8 9AG, UK.
Peter K
PK
Joshi
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02176, USA.
Gina M
GM
Peloso
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
Patrick
P
Deelen
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
Freerk
F
van Dijk
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam 1081BT, The Netherlands.
Gonneke
G
Willemsen
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam 1081BT, The Netherlands.
Eco J
EJ
de Geus
Department of Psychiatry, VU University Medical Center Amsterdam/GGZinGeest, EMGO+ Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam 1081HL, The Netherlands.
Yuri
Y
Milaneschi
Department of Psychiatry, VU University Medical Center Amsterdam/GGZinGeest, EMGO+ Institute for Health and Care Research, Neuroscience Campus Amsterdam, Amsterdam 1081HL, The Netherlands.
Brenda W J H
BW
Penninx
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
Laurent C
LC
Francioli
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
Androniki
A
Menelaou
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
Sara L
SL
Pulit
Department of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Fernando
F
Rivadeneira
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Albert
A
Hofman
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Ben A
BA
Oostra
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Oscar H
OH
Franco
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands.
Irene
I
Mateo Leach
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Marian
M
Beekman
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Anton J M
AJ
de Craen
Department of Genetical Statistics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
Hae-Won
HW
Uh
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
Holly
H
Trochet
Division of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
Lynne J
LJ
Hocking
Centre for Genomic and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
David J
DJ
Porteous
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
Naveed
N
Sattar
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Chris J
CJ
Packard
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
Brendan M
BM
Buckley
Department of Medicine, University of Washington, Seattle, Washington 98101, USA.
Jennifer A
JA
Brody
Department of Medicine, University of Washington, Seattle, Washington 98101, USA.
Joshua C
JC
Bis
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Jerome I
JI
Rotter
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
Josyf C
JC
Mychaleckyj
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland EH8 9AG, UK.
Harry
H
Campbell
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina NC 27599, USA.
Qing
Q
Duan
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina NC 27599, USA.
Leslie A
LA
Lange
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland EH8 9AG, UK.
James F
JF
Wilson
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
Caroline
C
Hayward
Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
Ozren
O
Polasek
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
Veronique
V
Vitart
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland EH8 9AG, UK.
Igor
I
Rudan
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
Alan F
AF
Wright
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
Stephen S
SS
Rich
Department of Medicine and Epidemiology, University of Washington, Seattle, Washington 98101, USA.
Bruce M
BM
Psaty
Department of Genetics and Biostatistics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Ingrid B
IB
Borecki
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
Patricia M
PM
Kearney
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
David J
DJ
Stott
1] Department of Biostatistics, Boston U School of Public Health, Boston, Massachusetts 02118, USA [2] Framingham Heart Study, Framingham, Massachusetts 01702, USA.
L
L
Adrienne Cupples
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
J Wouter
JW
Jukema
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, The Netherlands.
Pim
P
van der Harst
Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Eric J
EJ
Sijbrands
Department of Biological Psychology, VU University Amsterdam and EMGO+ Institute for Health and Care Research, Amsterdam 1081BT, The Netherlands.
Jouke-Jan
JJ
Hottenga
Department of Epidemiology and Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Andre G
AG
Uitterlinden
Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
Morris A
MA
Swertz
Department of Human Genetics, Leiden University Medical Center, Leiden P.O. Box 9600, 2300 RC, The Netherlands.
Gert-Jan B
GJ
van Ommen
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.
Paul I W
PI
de Bakker
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
P
P
Eline Slagboom
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands.
Dorret I
DI
Boomsma
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
Cisca
C
Wijmenga
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
Cornelia M
CM
van Duijn
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D009426:Netherlands
C434046:ABCA6 protein, human; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol