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

Xin Sheng; Yuting Guan; Ziyuan Ma; Junnan Wu; Hongbo Liu; Chengxiang Qiu; Steven Vitale; Zhen Miao; Matthew J Seasock; Matthew Palmer; Myung K Shin; Kevin L Duffin; Steven S Pullen; Todd L Edwards; Jacklyn N Hellwege; Adriana M Hung; Mingyao Li; Benjamin F Voight; Thomas M Coffman; Christopher D Brown; Katalin Susztak

doi:10.1038/s41588-021-00909-9

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

Nat Genet. 2021 Sep;53(9):1322-1333. doi: 10.1038/s41588-021-00909-9. Epub 2021 Aug 12.

Authors

Xin Sheng^#^{1

2

3}, Yuting Guan^#^{1

2

3}, Ziyuan Ma^{1

2

3}, Junnan Wu^{1

2

3}, Hongbo Liu^{1

2

3}, Chengxiang Qiu^{1

2

3}, Steven Vitale^{1

2

3}, Zhen Miao^{1

2

3}, Matthew J Seasock^{1

2

3}, Matthew Palmer⁴, Myung K Shin⁵, Kevin L Duffin⁶, Steven S Pullen⁷, Todd L Edwards⁸, Jacklyn N Hellwege⁸, Adriana M Hung⁹, Mingyao Li¹⁰, Benjamin F Voight^{2

3

11

12}, Thomas M Coffman¹³, Christopher D Brown³, Katalin Susztak^{14

15

16}

Affiliations

¹ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
² Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
⁵ Merck & Co., Inc, Kenilworth, NJ, USA.
⁶ Eli Lilly and Company Lilly Corporate Center, Indianapolis, IN, USA.
⁷ Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹¹ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹² Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
¹⁴ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁵ Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁶ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Chromosome Mapping
Endothelial Cells / pathology
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Genotype
High-Throughput Nucleotide Sequencing
Humans
Hypertension / genetics*
Kidney Tubules, Distal / pathology*
Kidney Tubules, Proximal / pathology*
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci / genetics*
Quantitative Trait, Heritable
Renal Insufficiency, Chronic / genetics*
Renal Insufficiency, Chronic / pathology
Sequence Analysis, RNA
Single-Cell Analysis

Associated data

figshare/10.6084/m9.figshare.14718015.v1

Abstract

Publication types

MeSH terms

Associated data

Grants and funding