Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation
The genetic regulation of Akr1e1 expression is reconstructed based on relationships observed across the three tissues. Distal-eQTL were detected in all tissues at similar levels of significance. A local-eQTL for Zfp985 that is proximal to the Akr1e1 distal-eQTL was observed in lung, and Zfp985 expression was detected as an anti-correlated mediator of the distal-eQTL, consistent with ZFP985 suppressing Akr1e1 expression. The chromatin site proximal to the Akr1e1 TSS has a distal-cQTL detected in kidney. Chromatin accessibility at the site was found to be a significant mediator of Akr1e1 expression. Combining associations across tissues supports a biological model whereby ZFP985, whose gene is expressed in mice with NOD, NZO, PWK, and WSB haplotypes, silences Akr1e1 through KRAB domain-induced chromatin remodeling. QTL and mediation genome scans are included, along with sequence phenotypes as interquartile ranges categorized according to most likely diplotype, and modeled haplotype effects fit as BLUPs. The relative magnitudes of the QTL effect sizes and mediation scores are consistent with the proposed model, with Zfp985 local-eQTL > distal-cQTL > Akr1e1 distal-eQTL, and chromatin mediation > mediation through Zfp985 expression.