Genetic control of the HDL proteome

Nathalie Pamir; Calvin Pan; Deanna L. Plubell; Patrick M. Hutchins; Chongren Tang; Jake Wimberger; Angela Irwin; Thomas Q. de Aguiar Vallim; Jay W. Heinecke; Aldons J. Lusis

Loci contributing to variations in protein levels (protein QTLs or pQTLs) or hepatic transcript levels of the proteins (expression QTLs or eQTLs) were mapped using the FAST LMN, an association algorithm with a mixed model component to correct for population structure. Association analysis was performed using about 200,000 informative SNPs (Bennett et al., 2010) , spaced throughout the genome (Table 2 ). Hepatic transcript levels were from a previous survey of the HMDP maintained on the same chow diet as in this study (Bennett et al., 2010) . Loci averaged 500 kb to 2 Mb in size and in most cases contained 1 to 20 genes within a linkage disequilibrium (LD) block, an improvement of more than an order of magnitude as compared to traditional linkage analysis in mice (typically a resolution of 10 to 20 Mb) (Flint et al., 2005) . Loci mapping within 1Mb of the gene are termed "local" QTL, suggesting that they probably act in cis. For example, promoter or enhancer variants would act in cis. Loci mapping greater than 1Mb from the gene of interest are termed "distal", implying that they act in trans, presumably mediated by a diffusible factor such as a transcription factor (Table 2 and Supplemental Table 2 ). We applied a significance filter of P=10 -3 and 10 -6 to identify suggestive cis and trans QTLs respectively.