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Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments
- Source :
- Nat Genet
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Linkage disequilibrium
Genotype
Quantitative Trait Loci
Genome-wide association study
Computational biology
Biology
Quantitative trait locus
Kidney
Polymorphism, Single Nucleotide
Article
Kidney Tubules, Proximal
Quantitative Trait, Heritable
Genetics
medicine
Humans
Genetic Predisposition to Disease
Renal Insufficiency, Chronic
Kidney Tubules, Distal
Gene
Genetic association
Base Sequence
Sequence Analysis, RNA
Chromosome Mapping
Endothelial Cells
High-Throughput Nucleotide Sequencing
medicine.disease
Genetic architecture
Hypertension
Expression quantitative trait loci
Single-Cell Analysis
Genetic Background
Genome-Wide Association Study
Kidney disease
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nat Genet
- Accession number :
- edsair.doi.dedup.....811c90ea7197028fb174cd66634d8857