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A catalog of genetic loci associated with kidney function from analyses of a million individuals
Univ Freiburg, Fac Med, Dept Biometry Epidemiol & Med Bioinformat, Inst Genet Epidemiol, Freiburg, Germany;Univ Freiburg, Med Ctr, Freiburg, Germany;Univ Freiburg, Fac Med, Dept Med 4, Renal Div, Freiburg, Germany.
Univ Freiburg, Fac Med, Dept Biometry Epidemiol & Med Bioinformat, Inst Genet Epidemiol, Freiburg, Germany;Univ Freiburg, Med Ctr, Freiburg, Germany.
Univ Utah, Dept Med, Div Nephrol & Hypertens, Salt Lake City, UT 84112 USA.ORCID iD: 0000-0002-3839-0281
GlaxoSmithKline, Target Sci Genet, Collegeville, PA USA.
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 51, no 6, p. 957-972
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Medical Genetics
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URN: urn:nbn:se:uu:diva-387933DOI: 10.1038/s41588-019-0407-xISI: 000469996900008PubMedID: 31152163OAI: oai:DiVA.org:uu-387933DiVA, id: diva2:1331152
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved

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Giedraitis, VilmantasIngelsson, ErikLind, LarsWallentin, Lars

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