Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease

被引:94
作者
Liu, Hongbo [1 ,2 ,3 ]
Doke, Tomohito [1 ,2 ,3 ]
Guo, Dong [4 ]
Sheng, Xin [1 ,2 ,3 ]
Ma, Ziyuan [1 ,2 ,3 ]
Park, Joseph [3 ,5 ]
Vy, Ha My T. [6 ,7 ]
Nadkarni, Girish N. [6 ,7 ,8 ,9 ]
Abedini, Amin [1 ,2 ,3 ]
Miao, Zhen [1 ,2 ,3 ]
Palmer, Matthew [10 ]
Voight, Benjamin F. [2 ,3 ,11 ,12 ]
Li, Hongzhe [13 ,14 ]
Brown, Christopher D. [3 ]
Ritchie, Marylyn D. [3 ]
Shu, Yan [4 ]
Susztak, Katalin [1 ,2 ,3 ]
机构
[1] Univ Penn, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA
[2] Univ Penn, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
[4] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA
[5] Univ Penn, Inst Biomed Informat, Perelman Sch Med, Philadelphia, PA 19104 USA
[6] Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA
[7] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
[8] Icahn Sch Med Mt Sinai, Hasso Plattner Inst Digital Hlth, New York, NY 10029 USA
[9] Icahn Sch Med Mt Sinai, Mt Sinai Clin Intelligence Ctr, New York, NY 10029 USA
[10] Hosp Univ Penn, Pathol & Lab Med, 3400 Spruce St, Philadelphia, PA 19104 USA
[11] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA
[12] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[13] Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA
[14] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA
关键词
INTEGRATIVE ANALYSIS; RENAL SECRETION; ASSOCIATION; EXPRESSION; ACCUMULATION; DEFICIENCY; MULTIDRUG; THOUSANDS; GENOTYPE; GWAS;
D O I
10.1038/s41588-022-01097-w
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.
引用
收藏
页码:950 / +
页数:37
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