Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Using glomerular (GLOM) and tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered eQTLs by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an “integrative prior” for Bayesian statistical fine mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.

Integrative analysis using cell-specific cis-regulatory element (CRE) maps can be improved with direct evidence of gene regulation by open chromatin regions. 10X Multiome Assay allows simultaneous detection of gene expression and chromatin state from the same cell and thus can identify putative regulatory elements directly linked to gene expression. We are optimizing 10X Multiome assays for use in nephrectomy and pediatric kidney biopsies to better map gene regulation, specifically in pediatric nephrotic syndrome (NS).