Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Gabriel B Loeb^{1

2}, Pooja Kathail³, Richard W Shuai⁴, Ryan Chung³, Reinier J Grona^{5

6}, Sailaja Peddada^{7

8}, Volkan Sevim^{7

9}, Scot Federman^{7

8}, Karl Mader^{7

8}, Audrey Y Chu¹⁰, Jonathan Davitte¹¹, Juan Du¹², Alexander R Gupta¹², Chun Jimmie Ye^{13

14

15}, Shawn Shafer^{7

9}, Laralynne Przybyla^{7

8}, Radu Rapiteanu¹⁶, Nilah M Ioannidis^{3

4

17}, Jeremy F Reiter^{18

19

20}

Affiliations

¹ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
² Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
³ Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
⁴ Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA, USA.
⁵ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁶ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁷ Laboratory for Genomics Research, San Francisco, CA, USA.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁹ Target Discovery, GSK, San Francisco, CA, USA.
¹⁰ Human Genetics and Genomics, GSK, Cambridge, MA, USA.
¹¹ Human Genetics and Genomics, GSK, Collegeville, PA, USA.
¹² Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹³ Division of Rheumatology, Department of Medicine; Bakar Computational Health Sciences Institute; Parker Institute for Cancer Immunotherapy; Institute for Human Genetics; Department of Epidemiology & Biostatistics; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
¹⁴ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
¹⁵ Arc Institute, Palo Alto, CA, USA.
¹⁶ Genome Biology, Research Technologies, GSK, Stevenage, UK.
¹⁷ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁸ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.
¹⁹ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.
²⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.

PMID: 39256582
DOI: 10.1038/s41588-024-01904-6

Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Gabriel B Loeb et al. Nat Genet. 2024 Oct.

. 2024 Oct;56(10):2078-2092.

doi: 10.1038/s41588-024-01904-6. Epub 2024 Sep 10.

Authors

Affiliations

¹ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
² Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Gabriel.Loeb@ucsf.edu.
³ Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
⁴ Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA, USA.
⁵ Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁶ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁷ Laboratory for Genomics Research, San Francisco, CA, USA.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁹ Target Discovery, GSK, San Francisco, CA, USA.
¹⁰ Human Genetics and Genomics, GSK, Cambridge, MA, USA.
¹¹ Human Genetics and Genomics, GSK, Collegeville, PA, USA.
¹² Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹³ Division of Rheumatology, Department of Medicine; Bakar Computational Health Sciences Institute; Parker Institute for Cancer Immunotherapy; Institute for Human Genetics; Department of Epidemiology & Biostatistics; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
¹⁴ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
¹⁵ Arc Institute, Palo Alto, CA, USA.
¹⁶ Genome Biology, Research Technologies, GSK, Stevenage, UK.
¹⁷ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁸ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.
¹⁹ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.
²⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA. Jeremy.Reiter@ucsf.edu.

PMID: 39256582
DOI: 10.1038/s41588-024-01904-6

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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Update of

Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function.
Loeb GB, Kathail P, Shuai R, Chung R, Grona RJ, Peddada S, Sevim V, Federman S, Mader K, Chu A, Davitte J, Du J, Gupta AR, Ye CJ, Shafer S, Przybyla L, Rapiteanu R, Ioannidis N, Reiter JF. Loeb GB, et al. bioRxiv [Preprint]. 2024 Jun 22:2024.06.18.599625. doi: 10.1101/2024.06.18.599625. bioRxiv. 2024. Update in: Nat Genet. 2024 Oct;56(10):2078-2092. doi: 10.1038/s41588-024-01904-6. PMID: 38948875 Free PMC article. Updated. Preprint.

References

1. Dantzler, W. H. Comparative Physiology of the Vertebrate Kidney (Springer Science & Business Media, 2012).
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1. Arpegård, J. et al. Comparison of heritability of cystatin C- and creatinine-based estimates of kidney function and their relation to heritability of cardiovascular disease. J. Am. Heart Assoc. 4, e001467 (2015). - PubMed - PMC
1. Raggi, P. et al. Heritability of renal function and inflammatory markers in adult male twins. Am. J. Nephrol. 32, 317–323 (2010). - PubMed - PMC

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Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Affiliations

Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function

Authors

Affiliations

Abstract

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous