Identification of context-dependent expression quantitative trait loci in whole blood.
Zhernakova DV., Deelen P., Vermaat M., van Iterson M., van Galen M., Arindrarto W., van 't Hof P., Mei H., van Dijk F., Westra H-J., Bonder MJ., van Rooij J., Verkerk M., Jhamai PM., Moed M., Kielbasa SM., Bot J., Nooren I., Pool R., van Dongen J., Hottenga JJ., Stehouwer CDA., van der Kallen CJH., Schalkwijk CG., Zhernakova A., Li Y., Tigchelaar EF., de Klein N., Beekman M., Deelen J., van Heemst D., van den Berg LH., Hofman A., Uitterlinden AG., van Greevenbroek MMJ., Veldink JH., Boomsma DI., van Duijn CM., Wijmenga C., Slagboom PE., Swertz MA., Isaacs A., van Meurs JBJ., Jansen R., Heijmans BT., 't Hoen PAC., Franke L.
Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs.