The availability of multi-omic data from the same individuals enabled us to go beyond “overlap analyses” (Figure 4A) and to investigate the cascading effect of genetic variation through the measured regulatory genomics layers. Specifically, we investigated whether the effect of a regulatory cis xQTL SNP is mechanistically mediated through its impact on epigenetic modification or gene expression using the casual inference test (CIT)35. This analysis was performed on 10,897 xQTL SNPs (impacting 629 genes based on the eQTL analysis) that are associated with all three molecular phenotypes, as only such SNPs satisfy the precondition for mediation analysis. With this analysis, we distinguished between three models for propagation of information from genetic variation: 1) independent effects of a SNP on cis gene expression and the cis epigenetic landscape (independent model or IM), 2) a propagation path from SNP to gene expression via epigenetic modifications (epigenetic mediation model or EM), or 3) a propagation path from SNP to the epigenome (namely DNA methylation) via gene expression (transcription mediation model or TM) (Figure 4B).
