Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

Nat Commun. 2018 Nov 22;9(1):4800. doi: 10.1038/s41467-018-07260-4.

Abstract

Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Profiling
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Kidney / metabolism
  • Kidney / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology