Fig. 6. Plasma and urine implicate distinct causal variants and bile acid metabolites in the SLC10A2 locus.

a, The SLC10A2 locus contains two metabolite- and matrix-specific mQTLs. b, Systematic exploration of the effect of the urine mQTL rs16961281 (outer two bands) and the plasma mQTL rs55971546 (inner two bands) on levels of 39 bile acids quantified in plasma (red frames) and urine (blue frames) from their respective GWAS showed a urine-specific inverse association of the urine mQTL with glycocholate as well as other known substrates of the bile acid transporter encoded by SLC10A2 in urine but not in plasma. The plasma mQTL was positively associated with specific, sulfated bile acids in plasma, and this metabolomic footprint was propagated to urine likely via glomerular filtration. The direction and magnitude of the modeled minor alleles on bile acid levels is color coded; dot size corresponds to significance levels. c, RNA-seq shows that SLC10A2 expression is specific to the kidney cortex (plotted using pyGenomeTracks version 3.7). ATAC-seq highlights cortex-pronounced active chromatin that directly intersects with the fine-mapped urine mQTL rs16961281 (credible set size = 1), located in the 5′ untranslated region, flanking the active transcription start site (TSSFInk, chromatin state band). RNA-seq and ATAC-seq tracks are an overlay of signal from three different tissue donors; chromatin states were derived from histone ChIP–seq data (see Extended Data Fig. 9 for the chromatin state legend; Methods). d, The findings for the urine-specific mQTL suggest that urine is the appropriate matrix to detect the effect of a minor allele at a regulatory variant that increases expression of SLC10A2 in the kidney cortex, leading to lower urine levels of the ASBT substrate glycocholate through reabsorption, which translates into lower risk of gallstone disease. GoF, gain of function with respect to ASBT-mediated transport.