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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.

Original publication

DOI

10.1038/s41588-019-0407-x

Type

Journal article

Journal

Nature genetics

Publication Date

06/2019

Volume

51

Pages

957 - 972

Addresses

Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.

Keywords

Lifelines Cohort Study, V. A. Million Veteran Program, Humans, Genetic Predisposition to Disease, Kidney Function Tests, Glomerular Filtration Rate, Chromosome Mapping, Inheritance Patterns, Quantitative Trait, Heritable, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, European Continental Ancestry Group, Renal Insufficiency, Chronic, Genome-Wide Association Study, Genetic Association Studies, Uromodulin