Rare mutations associating with serum creatinine and chronic kidney disease. G. Sveinbjornsson1, E. Mikaelsdottir1, R. Palsson2,3, O. S. Indridason3, H. Holm1, A. Jonasdottir1, A. Helgason1,4, S. Sigurdsson1, A. Jonasdottir1, A. Sigurdsson1, G. I. Eyjolfsson5, O. Sigurdardottir6, O. T. Magnusson1, A. Kong1,7, G. Masson1, P. Sulem1, I. Olafsson8, U. Thorsteinsdottir1,2, D. F. Gudbjartsson1,7, K. Stefansson1,2 1) DeCode Genetics, Reykjavik, Reykjavik, Iceland; 2) Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; 3) Internal Medicine Services, Landspitali - The National University Hospital of Iceland, 101 Reykjavik, Iceland,; 4) Department of Anthropology, University of Iceland, 101 Reykjavik, Iceland; 5) Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), 109 Reykjavik, Iceland; 6) Department of Clinical Biochemistry, Akureyri Hospital, 600 Akureyri, Iceland,; 7) School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland,; 8) Department of Clinical Biochemistry, The National University Hospital of Iceland, 101 Reykjavík, Iceland.

   Chronic kidney disease (CKD) is a term applied to irreversible loss of kidney function and is a serious public health problem. It is diagnosed through the measurement of serum creatinine (SCr) which reflects glomerular filtration rate. Here, we impute sequence variants identified by sequencing the whole genomes of 2,230 Icelanders into 81,656 chip-typed individuals and 112,630 relatives of chip-typed individuals with SCr measurements. In addition to replicating established loci, we discovered missense and loss of function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45, SLC47A1) and two E3 ubiquitin ligases (RNF186, RNF128). With SCr effects of four variants between 0.085 and 0.129 standard deviations these rare variants have a greater impact on SCr than the previously reported common variants with a maximum effect of 0.069. We tested the variants associating with SCr for association with CKD in a sample of 15,594 Icelandic cases and 291,420 controls and found significant associations at three of them. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease.

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