Fig. 6. Analysis human liver eQTLs uncovers TMEM147 and ENPP7 as effector transcripts of ICP susceptibility.

a, d LocusZoom⁸⁶ plots showing the association signals at TMEM147 and ENPP7, 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. PP_func, functional posterior probability calculated using PAINTOR¹⁷. CADD, combined annotation-dependent depletion. Overlap of ICP-associated variants in these two loci with adult liver accessible chromatin sites enabled the prioritization of two ICP regulatory variants in intronic regions of GAPDHS (rs4806173) (a) and ENPP7 (rs9916601) (d). b, e The ICP variants prioritized with functional liver chromatin annotations are eQTLs in liver tissue and pinpoint TMEM147 and ENPP7 as effector transcripts in these loci. 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 FastQTL⁸⁶ are shown. Liver eQTL plots were retrieved from GTEx³⁴ [GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2)]. We note that GAPDHS is a testis-specific gene and its interrogation as an eGene for rs4806173 was therefore not possible (b). c The ICP risk allele of rs4806173 (G), which associates with less transcription of TMEM147, is predicted to create a binding site for glucocorticoid receptors, a family of context-dependent transcriptional regulators that can act as either activators or repressors⁸⁷.