In this study we illustrate that eQTL analysis of expression data obtained from highly purified primary cells enriches eQTL identification and reveals underlying cellular specific complexity not appreciable from mixed tissue. It is clear that whilst many eQTL with large effect sizes are shared across cells, the majority of eQTL in primary tissue are cell-specific. The degree to which a single variant can associate with the expression of different genes in monocytes and B-cells is particularly striking. It is probable that analysis of further divergent primary cell populations will increase the number of examples of such cell-specific eQTL. The delineation of cell-directional eQTLs is also of importance; in the case of those observed with SELL, which encodes a membrane protein involved in cellular recruitment to areas of inflammation, the intriguing possibility is raised that a polymorphism may influence the predominant cell subset recruited.
This study reveals trans-eQTLs possess an even higher degree of cellular autonomy than cis, reflecting them manifesting as products of upstream gene expression and cellular cross-talk. Notably, we identify novel master-regulatory regions specific to monocytes via LYZ
and B-cells via the expression of KLF4
. The functional implications with respect to infectious disease susceptibility of the multi-locus LYZ
eQTL remain to be explored, but the existence of several genes including ERAP2
, encoding an aminopeptidase involved in the loading of class I MHC molecules55
as well as RAB27A
, encoding a GTPase critical to the membranous tethering of secretory lysosomes56
, would suggest this eQTL may impact upon antigen presentation. The identification of B-cell specific trans-eQTLs to rs11717139, a locus with reproducible association to autoimmune diseases, in genes with putative roles in cell-cycle and apoptosis provides novel candidate genes for analysis in autoimmune disease susceptibility. B-cells are intrinsically prone to apoptosis providing protection against the generation of self-reactive antibodies. Regulation of genes involved in apoptosis would therefore be predicted to alter this process and predispose to autoimmunity57
. It is notable that these genes do not have strong cis-eQTLs which otherwise might be expected to be disease associated.
Finally, we demonstrate for the first time the possession of specific HLA
alleles regulates gene expression in trans in a cell specific manner. The monocyte specific trans association of AOAH
expression to the possession of DRB1*04 , *07 and *09 alleles is particularly intriguing. Only these DRB1 alleles are associated with expression of HLA-DRB4
, encoding the DR53 superantigen58
. The reduced expression of AOAH
, an enzyme that hydrolyses the potent innate immune stimulant lipopolysaccharide, in monocytes might be anticipated to pre-dispose towards inflammation. Whether the further association of ARHGAP24
, encoding a protein involved in actin remodelling59
, a requirement for monocyte spreading and locomotion60
is secondary to reduced AOAH
expression will require further investigation. This study demonstrates that healthy individuals possess cell specific expression signatures attributable to HLA
allele carriage, reflecting the overwhelming importance HLA status plays upon everyday immune interactions.
Comparative analysis of highly pure cell subsets has the potential to unearth added intricacy in the nature of eQTLs, highlighting that the majority act in a cell specific manner and many eQTLs will likely remain undiscovered if analysis focuses on heterogeneous tissues. This study adds strong evidence to support the concept that a large number of eQTL function in a highly context specific manner in vivo and provide a plausible explanation for a degree of disease susceptibility.