Fig. 1: rs143348853 indel activates the AXIN2 VCM in LCLs.
a Workflow to evaluate impactful genetic variants using the VCM concept and Venn diagram of the significant variants considering an FDR ≤ 10% for VCM activity (vcmQTL), PU.1 binding (bQTL) and gene expression (eQTL). b (Top) Genomic view centered on the AXIN2-containing TAD using the 3D Genome Browser110 showing GM12878 HiC interactions from Rao et al., 201453 and GM12878 TADs from Beekman et al., 201872. (Bottom) Beta values representing the genetic effect of rs143348853 on different molecular phenotypes (PU.1, H3K27ac, H3K4me1, H3K4me3, RPB2 ChIP-seq, and ATAC-seq signals; FDR < 0.05 values are colored in red) and consensus VCMs. See Supplementary Fig. 1b for beta values for each molecular phenotype. c IGV111 view of the AXIN2 VCM region showing the consensus AXIN2 VCM and profiles for the studied molecular phenotypes from two different individual LCLs representing the rs143348853 homozygous REF and ALT genotypes. Meta peaks are displayed below each track. The shown regulatory hierarchy across the ATAC-seq peaks (visualized as unidirectional arrows) was inferred from the directed acyclic graph information from Kumasaka et al., 201816. Finally, the five principal AXIN2 LCL enhancer regions are annotated in green according to H3K4me1 and H3K27ac overlap, while the hypothesized “lead” enhancer is marked in dark green. d Boxplots showing different molecular phenotypes for each rs143348853 genotype in LCLs: AXIN2 mRNA expression, the activity of the AXIN2 VCM as measured by the first principal component analysis value (PC1) on all correlated histone marks embedded in the AXIN2 VCM, and PU.1 binding (peak id 1036) and ATAC-seq signal (peak id 254430) for the rs143348853-overlapping peaks. n indicates the number of considered individual LCL samples and P indicates the p-value from a linear regression model. Boxes indicate the IQR (25–75%) and the box center indicates the median. Whiskers represent the minimum or maximum values of no further than 1.5 times the IQR for both the top and bottom of the box.
