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

LifeLines Cohort Study

Research output: Contribution to journalArticle

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 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 languageEnglish
Pages (from-to)957-972
Number of pages16
JournalNature Genetics
Volume51
Issue number6
DOIs
Publication statusPublished - Jun 2019

Fingerprint

Genetic Loci
Kidney
Glomerular Filtration Rate
Chronic Renal Insufficiency
Translational Medical Research
Genome-Wide Association Study
Blood Urea Nitrogen
Genes
Meta-Analysis
Public Health
Phenotype
Gene Expression

Keywords

  • Chromosome Mapping
  • European Continental Ancestry Group
  • Genetic Association Studies/methods
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glomerular Filtration Rate
  • Humans
  • Inheritance Patterns
  • Kidney Function Tests
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Quantitative Trait, Heritable
  • Renal Insufficiency, Chronic/genetics
  • Uromodulin/urine

Cite this

A catalog of genetic loci associated with kidney function from analyses of a million individuals. / LifeLines Cohort Study.

In: Nature Genetics, Vol. 51, No. 6, 06.2019, p. 957-972.

Research output: Contribution to journalArticle

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KW - Genetic Association Studies/methods

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KW - Inheritance Patterns

KW - Kidney Function Tests

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Quantitative Trait, Heritable

KW - Renal Insufficiency, Chronic/genetics

KW - Uromodulin/urine

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JO - Nature Genetics

JF - Nature Genetics

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