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Rare mutations associating with serum creatinine and chronic kidney disease.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2014 Dec 20; Vol. 23 (25), pp. 6935-43. Date of Electronic Publication: 2014 Jul 31. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Adolescent
Adult
Aged
Alleles
Case-Control Studies
Female
Gene Frequency
Genetic Loci
Genome-Wide Association Study
Genotype
Glomerular Filtration Rate
Humans
INDEL Mutation
Iceland
Male
Middle Aged
Polymorphism, Single Nucleotide
Renal Insufficiency, Chronic blood
Renal Insufficiency, Chronic pathology
Amino Acid Transport Systems, Neutral genetics
Creatinine blood
Membrane Proteins genetics
Mitochondrial Proteins genetics
Organic Cation Transport Proteins genetics
Renal Insufficiency, Chronic genetics
Ubiquitin-Protein Ligases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 23
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25082825
- Full Text :
- https://doi.org/10.1093/hmg/ddu399