LDL-cholesterol concentrations: a genome-wide association study.
BACKGROUND
LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations.


METHODS
We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations.


RESULTS
In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L.


CONCLUSIONS
We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.
Sandhu
Manjinder S
MS
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK. manj.sandhu@srl.cam.ac.uk
Waterworth
Dawn M
DM
Debenham
Sally L
SL
Wheeler
Eleanor
E
Papadakis
Konstantinos
K
Zhao
Jing Hua
JH
Song
Kijoung
K
Yuan
Xin
X
Johnson
Toby
T
Ashford
Sofie
S
Inouye
Michael
M
Luben
Robert
R
Sims
Matthew
M
Hadley
David
D
McArdle
Wendy
W
Barter
Philip
P
Kesäniemi
Y Antero
YA
Mahley
Robert W
RW
McPherson
Ruth
R
Grundy
Scott M
SM
Bingham
Sheila A
SA
Khaw
Kay-Tee
KT
Loos
Ruth J F
RJ
Waeber
Gérard
G
Barroso
Inês
I
Strachan
David P
DP
Deloukas
Panagiotis
P
Vollenweider
Peter
P
Wareham
Nicholas J
NJ
Mooser
Vincent
V
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics* / Q000502:physiology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016036:Seroepidemiologic Studies; D044465:White People / Q000235:genetics
D008078:Cholesterol, LDL