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A catalog of genetic loci associated with kidney function from analyses of a million individuals

Wuttke, Matthias; Almgren, Peter LU ; Lindgren, Cecilia M LU ; Melander, Olle LU ; Orho-Melander, Marju LU ; Perola, Markus LU ; Schulz, Christina-Alexandra LU ; Thomsen, Hauke LU ; Wallentin, Lars LU and , , et al. (2019) In Nature Genetics 51(6). p.957-972
Abstract

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization... (More)

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

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Nature Genetics
volume
51
issue
6
pages
16 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85066607502
ISSN
1546-1718
DOI
10.1038/s41588-019-0407-x
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English
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yes
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3824b3b2-b570-4938-bfa2-d2ac1a69da65
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2019-06-10 15:23:37
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2019-11-13 05:35:39
@article{3824b3b2-b570-4938-bfa2-d2ac1a69da65,
  abstract     = {<p>Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.</p>},
  author       = {Wuttke, Matthias and Almgren, Peter and Lindgren, Cecilia M and Melander, Olle and Orho-Melander, Marju and Perola, Markus and Schulz, Christina-Alexandra and Thomsen, Hauke and Wallentin, Lars and ,  and Pattaro, Cristian},
  issn         = {1546-1718},
  language     = {eng},
  month        = {05},
  number       = {6},
  pages        = {957--972},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {A catalog of genetic loci associated with kidney function from analyses of a million individuals},
  url          = {http://dx.doi.org/10.1038/s41588-019-0407-x},
  volume       = {51},
  year         = {2019},
}