Rare mutations associating with serum creatinine and chronic kidney disease

Hum Mol Genet. 2014 Dec 20;23(25):6935-43. doi: 10.1093/hmg/ddu399. Epub 2014 Jul 31.


Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Amino Acid Transport Systems, Neutral / genetics*
  • Case-Control Studies
  • Creatinine / blood*
  • Female
  • Gene Frequency
  • Genetic Loci
  • Genome-Wide Association Study
  • Genotype
  • Glomerular Filtration Rate
  • Humans
  • INDEL Mutation
  • Iceland
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Organic Cation Transport Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology
  • Ubiquitin-Protein Ligases / genetics*


  • Amino Acid Transport Systems, Neutral
  • Membrane Proteins
  • Mitochondrial Proteins
  • Organic Cation Transport Proteins
  • SLC47A1 protein, human
  • SLC6A19 protein, human
  • Slc25a45 protein, human
  • Creatinine
  • RNF128 protein, human
  • RNF186 protein, human
  • Ubiquitin-Protein Ligases