Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease

被引：184

作者：

Qiu, Chengxiang ^{[1
]}

Huang, Shizheng ^{[1
]}

Park, Jihwan ^{[1
]}

Park, YoSon ^{[2
]}

Ko, Yi-An ^{[1
,2
]}

Seasock, Matthew J. ^{[1
]}

Bryer, Joshua S. ^{[1
]}

Xu, Xiang-Xi ^{[3
]}

Song, Wen-Chao ^{[4
]}

Palmer, Matthew ^{[5
]}

Hill, Jon ^{[6
]}

Guarnieri, Paolo ^{[6
]}

Hawkins, Julie ^{[6
]}

Boustany-Kari, Carine M. ^{[6
]}

Pullen, Steven S. ^{[6
]}

Brown, Christopher D. ^{[2
]}

Susztak, Katalin ^{[1
,2
]}

机构：

[1] Univ Penn, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Univ Miami, Miller Sch Med, Dept Cell Biol, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[4] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Pathol & Lab Med Hosp, Philadelphia, PA 19104 USA

[6] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 11期

关键词：

EPITHELIAL-CELLS; PROXIMAL TUBULE; HUMAN GENOME; EXPRESSION; RISK; VARIANT; GROWTH; BETA; IDENTIFICATION; METAANALYSIS;

D O I：

10.1038/s41591-018-0194-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-beta pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.

引用

页码：1721 / +

页数：14

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