title: Rare mutations associating with serum creatinine and chronic kidney disease.
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.
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Gardar
authors.initials: G
authors.lastname: Sveinbjornsson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Mikaelsdottir
authors.affiliation: Faculty of Medicine Internal Medicine Services.
authors.forename: Runolfur
authors.initials: R
authors.lastname: Palsson
authors.affiliation: Internal Medicine Services.
authors.forename: Olafur S
authors.initials: OS
authors.lastname: Indridason
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland Department of Anthropology.
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), 109 Reykjavik, Iceland and.
authors.forename: Gudmundur Ingi
authors.initials: GI
authors.lastname: Eyjolfsson
authors.affiliation: Department of Clinical Biochemistry, Akureyri Hospital, 600 Akureyri, Iceland.
authors.forename: Olof
authors.initials: O
authors.lastname: Sigurdardottir
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Olafur Th
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: Department of Clinical Biochemistry, Landspitali - The National University Hospital of Iceland, 101 Reykjavík, Iceland.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland Faculty of Medicine.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland daniel.gudbjartsson@decode.is kari.stefansson@decode.is.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE Genetics, 101 Reykjavik, Iceland Faculty of Medicine daniel.gudbjartsson@decode.is kari.stefansson@decode.is.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics*; D016022:Case-Control Studies; D003404:Creatinine / Q000097:blood*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D054643:INDEL Mutation; D007055:Iceland; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C491436:SLC6A19 protein, human; C000592571:Slc25a45 protein, human; D003404:Creatinine; C520250:RNF128 protein, human; C587047:RNF186 protein, human; D044767:Ubiquitin-Protein Ligases