title: LDL-cholesterol concentrations: a genome-wide association study.
abstract: 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.
authors.affiliation: Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK. manj.sandhu@srl.cam.ac.uk
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.forename: Sally L
authors.initials: SL
authors.lastname: Debenham
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Papadakis
authors.forename: Jing Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Kijoung
authors.initials: K
authors.lastname: Song
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.forename: Sofie
authors.initials: S
authors.lastname: Ashford
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.forename: Matthew
authors.initials: M
authors.lastname: Sims
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.forename: Wendy
authors.initials: W
authors.lastname: McArdle
authors.forename: Philip
authors.initials: P
authors.lastname: Barter
authors.forename: Y Antero
authors.initials: YA
authors.lastname: Kesäniemi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mahley
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Grundy
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Bingham
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Deloukas
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Vincent
authors.initials: V
authors.lastname: Mooser
mesh_terms: 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
chemical_list: D008078:Cholesterol, LDL