The resolution of trans-acting genetic factors and associated gene networks is recognized to be highly informative but challenging (19, 28, 53). Treatment with innate immune stimuli reveals a number of marked trans-eQTL including regulatory hubs. This may reflect a synchronizing influence of stimulation on the expression patterns of monocytes, allowing underlying genetic influences to be defined by reducing stochastic variation at the individual cell level. Notably, we observe opposing quantitative effects of chronic LPS and IFNγ on the numbers of trans-associated genes to the MHC class II region that parallel underlying class II expression. These trans-eQTL are likely to arise from cis effects in the MHC and/or to specific human leukocyte antigen (HLA) alleles; however, elucidating the mechanisms underpinning this observation requires further investigation. Context-specific differential cis effects at other loci similarly are perceived to induce consequential trans networks as illustrated by those observed at IFNB1 and IRF2. These data support a model where identifying the genetic effects on a system requires the identification of a pathway, and any relevant effects of variation on upstream activation before the underlying impact of genetic variation and trans associations can be revealed.
