Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

• Published in: Nature genetics Vol. 53; no. 9; pp. 1322 - 1333
• Main Authors: Sheng, Xin, Guan, Yuting, Ma, Ziyuan, Wu, Junnan, Liu, Hongbo, Qiu, Chengxiang, Vitale, Steven, Miao, Zhen, Seasock, Matthew J., Palmer, Matthew, Shin, Myung K., Duffin, Kevin L., Pullen, Steven S., Edwards, Todd L., Hellwege, Jacklyn N., Hung, Adriana M., Li, Mingyao, Voight, Benjamin F., Coffman, Thomas M., Brown, Christopher D., Susztak, Katalin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2021; Nature Publishing Group
• Subjects: 631/208/176; 631/208/200; 692/699/1585/104; 692/699/75/243/785; Agriculture; Animal Genetics and Genomics; Antihypertensives; Base Sequence; Bayesian analysis; Biomedical and Life Sciences; Biomedicine; Blood pressure; Cancer Research; Chromatin; Chromosome Mapping; Endothelial cells; Endothelial Cells - pathology; Gene expression; Gene Function; Gene mapping; Gene sequencing; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype; Genotype & phenotype; Genotypes; Heritability; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Hypertension; Hypertension - genetics; Kidney diseases; Kidney Tubules, Distal - pathology; Kidney Tubules, Proximal - pathology; Kidneys; Linkage disequilibrium; Mapping; Metabolism; Next-generation sequencing; Pathogenesis; Polymorphism, Single Nucleotide - genetics; Proteins; Proximal tubules; Quantitative trait loci; Quantitative Trait Loci - genetics; Quantitative Trait, Heritable; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Sequence Analysis, RNA; Single-Cell Analysis; Transposase
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-021-00909-9

The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.
Cell-type-specific eQTL maps in the human kidney generated from the analysis of over 600 microdissected kidney samples, together with single-cell RNA sequencing and single-nucleus ATAC-seq, prioritize cell types influencing kidney function, hypertension and other traits.