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Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function.
Loeb, Gabriel B; Kathail, Pooja; Shuai, Richard W; Chung, Ryan; Grona, Reinier J; Peddada, Sailaja; Sevim, Volkan; Federman, Scot; Mader, Karl; Chu, Audrey Y; Davitte, Jonathan; Du, Juan; Gupta, Alexander R; Ye, Chun Jimmie; Shafer, Shawn; Przybyla, Laralynne; Rapiteanu, Radu; Ioannidis, Nilah M; Reiter, Jeremy F.
Afiliação
  • Loeb GB; Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
  • Kathail P; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
  • Shuai RW; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Chung R; Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA, USA.
  • Grona RJ; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Peddada S; Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Sevim V; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
  • Federman S; Laboratory for Genomics Research, San Francisco, CA, USA.
  • Mader K; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Chu AY; Laboratory for Genomics Research, San Francisco, CA, USA.
  • Davitte J; Target Discovery, GSK, San Francisco, CA, USA.
  • Du J; Laboratory for Genomics Research, San Francisco, CA, USA.
  • Gupta AR; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Ye CJ; Laboratory for Genomics Research, San Francisco, CA, USA.
  • Shafer S; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Przybyla L; Human Genetics and Genomics, GSK, Cambridge, MA, USA.
  • Rapiteanu R; Human Genetics and Genomics, GSK, Collegeville, PA, USA.
  • Ioannidis NM; Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
  • Reiter JF; Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Nat Genet ; 2024 Sep 10.
Article em En | MEDLINE | ID: mdl-39256582
ABSTRACT
Kidney failure, the decrease of kidney function below a threshold necessary to support life, is a major cause of morbidity and mortality. We performed a genome-wide association study (GWAS) of 406,504 individuals in the UK Biobank, identifying 430 loci affecting kidney function in middle-aged adults. To investigate the cell types affected by these loci, we integrated the GWAS with human kidney candidate cis-regulatory elements (cCREs) identified using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). Overall, 56% of kidney function heritability localized to kidney tubule epithelial cCREs and an additional 7% to kidney podocyte cCREs. Thus, most heritable differences in adult kidney function are a result of altered gene expression in these two cell types. Using enhancer assays, allele-specific scATAC-seq and machine learning, we found that many kidney function variants alter tubule epithelial cCRE chromatin accessibility and function. Using CRISPRi, we determined which genes some of these cCREs regulate, implicating NDRG1, CCNB1 and STC1 in human kidney function.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos