Skip to main content
. 2022 Aug 17;13:4840. doi: 10.1038/s41467-022-29931-z

Fig. 4. Three ABC transporter gene loci are associated with intrahepatic cholestasis of pregnancy (ICP).

Fig. 4

a, c, e LocusZoom61 plots showing the association signals at ABCG8, ABCB1/4, and DHRS9, respectively. The LocusZoom plots are as per Fig. 3 and association testing was performed as described in Fig. 1. At each locus, a single noncoding variant was prioritized as likely causal following the strategy outlined in Fig. 2. All epigenomic and transcriptomic datasets shown were retrieved from ENCODE18. Adult liver ATAC-seq peaks track (green regions) corresponds to regions accessible in at least two out of four ENCODE adult liver ATAC-seq (see Methods). 95% PP ICP variants, variants within the 95% genetic credible set in the ICP meta-analysis. LD ICP variants, variants with EUR r2 > 0.8 with the meta-analysis lead variant. PPfunc, functional posterior probability calculated using PAINTOR17. CADD, combined annotation-dependent depletion. a Zoomed inset shows a coding variant at ABCG8 overlapping a hepatic transcriptional enhancer, as revealed by strong H3K27ac enrichment and accessible chromatin in adult female liver tissue. Metadome analysis did not suggest that this variant affects protein function (see Supplementary Fig. 7). b Allele-specific effect of the prioritized risk variant rs4148211, assessed by Survey of Regulatory Elements (SuRE) in HepG2 cells31. The results suggest that the risk variant associates with decreased transcriptional activity. Mean signal and two-sided Wilcoxon rank-sum test. Previously determined 5% false-discovery rate threshold: P < 0.0017312131. Source data are provided as a Source Data file. c, e Zoomed insets show two prioritized regulatory risk variants for ICP: one affecting a hepatic enhancer between ABCB1 and ABCB4 (c), and one affecting a hepatic enhancer in an intron of DHRS9 (d). We note however that DHRS9 is not expressed in liver tissue, as shown in the strand-specific RNA-seq tracks. In contrast, ABCB11 is highly expressed in this tissue making it a likely effector transcript in this locus.