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

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. BrownKatalin Susztak

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

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.

Original language	English
Pages (from-to)	1322-1333
Number of pages	12
Journal	Nature Genetics
Volume	53
Issue number	9
DOIs	https://doi.org/10.1038/s41588-021-00909-9
State	Published - Sep 2021
Externally published	Yes

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Sheng, X., Guan, Y., Ma, Z., Wu, J., Liu, H., Qiu, C., Vitale, S., Miao, Z., Seasock, M. J., Palmer, M., Shin, M. K., Duffin, K. L., Pullen, S. S., Edwards, T. L., Hellwege, J. N., Hung, A. M., Li, M., Voight, B. F., Coffman, T. M., ... Susztak, K. (2021). Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments. Nature Genetics, 53(9), 1322-1333. https://doi.org/10.1038/s41588-021-00909-9

@article{79edd67f500347f7aee955ee8dd50efe,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = sep,

doi = "10.1038/s41588-021-00909-9",

language = "英语",

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journal = "Nature Genetics",

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Sheng, X, Guan, Y, Ma, Z, Wu, J, Liu, H, Qiu, C, Vitale, S, Miao, Z, Seasock, MJ, Palmer, M, Shin, MK, Duffin, KL, Pullen, SS, Edwards, TL, Hellwege, JN, Hung, AM, Li, M, Voight, BF, Coffman, TM, Brown, CD & Susztak, K 2021, 'Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments', Nature Genetics, vol. 53, no. 9, pp. 1322-1333. https://doi.org/10.1038/s41588-021-00909-9

TY - JOUR

T1 - Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments

AU - Sheng, Xin

AU - Guan, Yuting

AU - Ma, Ziyuan

AU - Wu, Junnan

AU - Liu, Hongbo

AU - Qiu, Chengxiang

AU - Vitale, Steven

AU - Miao, Zhen

AU - Seasock, Matthew J.

AU - Palmer, Matthew

AU - Shin, Myung K.

AU - Duffin, Kevin L.

AU - Pullen, Steven S.

AU - Edwards, Todd L.

AU - Hellwege, Jacklyn N.

AU - Hung, Adriana M.

AU - Li, Mingyao

AU - Voight, Benjamin F.

AU - Coffman, Thomas M.

AU - Brown, Christopher D.

AU - Susztak, Katalin

PY - 2021/9

Y1 - 2021/9

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AB - 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.

UR - https://www.scopus.com/pages/publications/85112717512

U2 - 10.1038/s41588-021-00909-9

DO - 10.1038/s41588-021-00909-9

M3 - 文章

C2 - 34385711

AN - SCOPUS:85112717512

SN - 1061-4036

VL - 53

SP - 1322

EP - 1333

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

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