title: Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol.
abstract: BACKGROUND
  Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs.
  
  
  RESULTS
  Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants.
  
  
  CONCLUSIONS
  Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Edmondson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
authors.forename: Amit V
authors.initials: AV
authors.lastname: Khera
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Derohannessian
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D008076:Cholesterol, HDL; D000090943:Delta-5 Fatty Acid Desaturase; C000716847:FADS1 protein, human