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 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 but also included low-frequency nonsynonymous SNPs.
Methods and Results
Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in three additional populations for a total meta-analysis in 7,857 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 suggestive of 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 five loci, including association with low frequency nonsynonymous variants.
Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts composed of extreme individuals may be efficiently used in a case-control discovery of quantitative traits.