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

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

doi:10.1038/s41588-021-00909-9

Cited by 112 publications

(90 citation statements)

References 99 publications

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“…Human kidneys were homogenized and single-nuclear suspension for snATAC sequencing (snATACseq) was prepared according to the manufacturer’s protocol (10X Genomics) as previously described ( 56 , 57 ). Quality control for constructed library was perform by an Agilent Bioanalyzer High Sensitivity DNA kit.…”

Section: Methodsmentioning

confidence: 99%

“…The libraries were sequenced on an Illumina HiSeq. The data processing and analysis were performed as previously described ( 57 ).…”

Section: Methodsmentioning

confidence: 99%

“…The likely causal SNP was prioritized by the following method: (i) reached genome-wide significance in eGFRcrea GWAS ( 5 ), (ii) reached genome-wide significance in human kidney eQTL for CASP9 ( 8 ), (iii) located in an open chromatin area in human kidney snATACseq data ( 57 ), and (iv) altered the expression of the target gene in CRISPR-Cas9 locus deletion experiments.…”

Section: Methodsmentioning

confidence: 99%

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Genome-wide association studies identify the role of caspase-9 in kidney disease

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Section: Methodsmentioning

confidence: 99%

“…The libraries were sequenced on an Illumina HiSeq. The data processing and analysis were performed as previously described ( 57 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genome-wide association studies identify the role of caspase-9 in kidney disease

et al. 2021

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“…Single-cell ATAC sequencing. We reanalyzed mouse snATAC-seq data (three healthy mouse kidneys; 16,887 nuclei) and human snATAC-seq data (two healthy human kidneys; 12,720 nuclei), as described earlier 41,60 .…”

Section: Data Availabilitymentioning

confidence: 99%

A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Guan

Liang

et al. 2021

Nat Commun

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Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.

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“…This type of analysis is natural to apply to single-cell experiments, since it assists in the interpretation of revealed cell classes. For example, in a 2021 study by Sheng et al, on single-cell characterisation over different cell types in kidneys, MAGMA was applied to gene expression data and S-LDSC was applied to the scATAC-seq data [231]. Both of these analyses uncovered enrichment by GWAS results for eGFR in proximal tubules of nephrons, which mirrors the complementary result obtained with enrichment GWAS for eGFR using LDSC-SEG on expression data in proximal tubules of nephrons [232].…”

Section: Interpretation Of Functional Annotations Using Gwas Resultsmentioning

confidence: 77%

Bench Research Informed by GWAS Results

Kondratyev

Алфимова

Golov

et al. 2021

Cells

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Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they are usually ‘highly polygenic’. The study of such traits presents a challenge for researchers, as the complex genetic architecture of such traits makes it nearly impossible to utilise many of the usual methods of reverse genetics, which often focus on specific genes. In recent years, thousands of genome-wide association studies (GWAS) were undertaken to explore the relationships between complex traits and a large number of genetic factors, most of which are characterised by tiny effects. In this review, we aim to familiarise ‘wet biologists’ with approaches for the interpretation of GWAS results, to clarify some issues that may seem counterintuitive and to assess the possibility of using GWAS results in experiments on various complex traits.

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

Cited by 112 publications

References 99 publications

Genome-wide association studies identify the role of caspase-9 in kidney disease

Genome-wide association studies identify the role of caspase-9 in kidney disease

A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

Bench Research Informed by GWAS Results

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