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

Fig. 5. GWAS meta-analysis of ICP reveals association signals affecting the bile acid homeostasis genes CYP7A1 and SULT2A1.

Fig. 5

a, d LocusZoom61 plots showing the association signals at CYP7A1 and SULT2A1, respectively. The LocusZoom plots are as per Fig. 3 and association testing was performed as described in Fig. 1. 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 PAINTOR. CADD, combined annotation-dependent depletion. a Functional fine-mapping with PAINTOR17 identified a single variant (rs10504255) with a posterior probability over 0.99 overlapping an active liver enhancer located between the CYP7A1 gene, which encodes the rate-limiting enzyme for bile acid synthesis, and UBXN2B. b, e GTEx34 [GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2)] human liver eQTLs identify the top prioritized variant in the CYP7A1 locus (rs10504255) as an eQTL associated with the eGene UBXN2B (b) and show that the SULT2A1 promoter ICP variant (rs296361) is an eQTL for both SULT2A1 and its downstream lncRNA LINC01595 (e). Violin plots represent the density distribution of the samples in each genotype (n for each genotype is indicated below in blue). Box plots show normalized gene expression in median (white line), first and third quartiles. Gene-level adjusted P values calculated with FastQTL85 are shown. c The risk allele of the ICP-associated variant rs10504255 (G) disrupts a DMRTA1-binding motif. We note that this allele also associates with weaker transactivation in liver tissue, as observed by eQTL analysis (b). d Overlap of ICP risk variants with adult liver accessible chromatin sites revealed one variant in the promoter of SULT2A1 (rs296361). f Transcription factor motif analysis revealed that the ICP variant rs296361 affects a motif for the SOX-D transcriptional repressor family.