Fig. 7: Primary human kidney tissue permits prioritization of causal variants in kidney-enriched genes implicated by mQTLs.
a, The locus highlighted in this figure contains an mQTL identified with both plasma and urine measurements of a metabolite. b, SLC13A3 transcript levels are particularly high in the kidney cortex and medulla among Genotype–Tissue Expression (GTEx) version 8 samples (nkidney cortex = 85, nkidney medulla = 4, nothers = 9–803; Methods). The dark bars in the violin plots mark the 25th and 75th percentiles. TPM, transcripts per million. c, RNA-seq shows that SLC13A3 is predominantly expressed in the kidney cortex. ATAC-seq highlights cortex-specific active chromatin around the rs6124828 index SNP, which was associated with malate, fumarate (both in plasma) and methylsuccinoylcarnitine (in plasma and urine). RNA-seq and ATAC-seq tracks are an overlay of signal from three different tissue samples (donors). Chromatin states derived from histone ChIP–seq data show an active enhancer state at the rs6124828 position (see Extended Data Fig. 9 for the chromatin state legend). The transcription factor (TF) motifs for HNF1A and HNF1B overlap rs6124828, and transcription factor ChIP–seq from HepG2 cells shows that the motifs are bound by both transcription factors. The minor A allele results in a higher predicted binding P value for HNF1A and HNF1B. d, Schematic representation of the effect of genotype at the mQTL rs6124828 on NaDC3-mediated metabolite transport and subsequent intracellular metabolism. Intermatrix colocalization of genetic associations with methylsuccinoylcarnitine suggests that its levels in urine may reflect filtration from plasma, but an exit at the apical membrane cannot be excluded.
