Despite the large number of eQTLs identified, the transcriptome of circulating monocytes, contrary to initial expectations [7]–[10], appeared of modest help to dissect the relationship between genome variability and complex human traits such as cardiovascular risk factors. One explanation for this finding might be that monocytes are not the most relevant cells for unravelling links between genome variation and the risk factors investigated. With regard to circulating lipids for example, only 28 of the 45 genes located in regions harbouring SNPs associated with circulating lipids in GWAS [24] were expressed in monocytes. The difficulty to corroborate the messenger paradigm in human clinical studies may also relate to the fact that the linear model of causality generally assumed to reflect the relation between genome variability, expression and phenotype may be too simplistic to account for a much more complex biological reality. The effects of genetic variants may be too weak to allow detection even in a study of this size. It is also important to keep in mind that most reported eSNPs are acting in cis, whereas trans eSNPs may actually be those that mainly drive the changes in gene expression that affect disease risk.
