Abstract
Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Coresh, J. et al. Prevalence of chronic kidney disease in the United States. J. Am. Med. Assoc. 298, 2038–2047 (2007).
Meguid El Nahas, A. & Bello, A.K. Chronic kidney disease: the global challenge. Lancet 365, 331–340 (2005).
Go, A.S., Chertow, G.M., Fan, D., McCulloch, C.E. & Hsu, C.Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).
Smith, D.H., Gullion, C.M., Nichols, G., Keith, D.S. & Brown, J.B. Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J. Am. Soc. Nephrol. 15, 1300–1306 (2004).
Levey, A.S. et al. Chronic kidney disease as a global public health problem: approaches and initiatives-a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 72, 247–259 (2007).
Fox, C.S. et al. Predictors of new-onset kidney disease in a community-based population. J. Am. Med. Assoc. 291, 844–850 (2004).
Fox, C.S. & Muntner, P. Trends in diabetes, high cholesterol, and hypertension in chronic kidney disease among U.S. adults: 1988–1994 to 1999–2004. Diabetes Care 31, 1337–1342 (2008).
Satko, S.G., Sedor, J.R., Iyengar, S.K. & Freedman, B.I. Familial clustering of chronic kidney disease. Semin. Dial. 20, 229–236 (2007).
Fox, C.S. et al. Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study. J. Am. Soc. Nephrol. 15, 2457–2461 (2004).
Kottgen, A. et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41, 712–717 (2009).
Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).
Göring, H.H. et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).
Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).
Kohjima, M. et al. PAR3β, a novel homologue of the cell polarity protein PAR3, localizes to tight junctions. Biochem. Biophys. Res. Commun. 299, 641–646 (2002).
Hayashi, M. & Araki, T. Caspase in renal development. Nephrol. Dial. Transplant. 17 Suppl 9, 8–10 (2002).
Hirschhorn, J.N. Genomewide association studies–illuminating biologic pathways. N. Engl. J. Med. 360, 1699–1701 (2009).
Johnson, A.D. & O'Donnell, C.J. An open access database of genome-wide association results. BMC Med. Genet. 10, 6 (2009).
Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).
Davenport, J.R. & Yoder, B.K. An incredible decade for the primary cilium: a look at a once-forgotten organelle. Am. J. Physiol. Renal Physiol. 289, F1159–F1169 (2005).
Plomin, R., Haworth, C.M. & Davis, O.S. Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878 (2009).
Monsees, G.M., Tamimi, R.M. & Kraft, P. Genome-wide association scans for secondary traits using case-control samples. Genet. Epidemiol. 33, 717–728 (2009).
Mattoo, A. & Goldfarb, D.S. Cystinuria. Semin. Nephrol. 28, 181–191 (2008).
Evan, A.P. et al. Renal crystal deposits and histopathology in patients with cystine stones. Kidney Int. 69, 2227–2235 (2006).
Feliubadaló, L. et al. Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis. Hum. Mol. Genet. 12, 2097–2108 (2003).
Prié, D. et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Engl. J. Med. 347, 983–991 (2002).
Magagnin, S. et al. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc. Natl. Acad. Sci. USA 90, 5979–5983 (1993).
Marshall, J.D. et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alstrom syndrome. Hum. Mutat. 28, 1114–1123 (2007).
Joy, T. et al. Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet J. Rare Dis. 2, 49 (2007).
Li, G. et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet. 3, e8 (2007).
Juhanson, P. et al. N-acetyltransferase 8, a positional candidate for blood pressure and renal regulation: resequencing, association and in silico study. BMC Med. Genet. 9, 25 (2008).
Nagai, J. et al. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am. J. Physiol. Renal Physiol. 289, F569–F576 (2005).
Hosaka, K. et al. Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells. Kidney Int. 75, 1308–1315 (2009).
Kao, W.H. et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat. Genet. 40, 1185–1192 (2008).
Kopp, J.B. et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 40, 1175–1184 (2008).
Eremina, V., Baelde, H.J. & Quaggin, S.E. Role of the VEGF–a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol. 106, 32–37 (2007).
Karihaloo, A. et al. Vascular endothelial growth factor induces branching morphogenesis/tubulogenesis in renal epithelial cells in a neuropilin-dependent fashion. Mol. Cell. Biol. 25, 7441–7448 (2005).
Iynedjian, P.B. Molecular physiology of mammalian glucokinase. Cell. Mol. Life Sci. 66, 27–42 (2009).
Gorivodsky, M. et al. Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. Dev. Biol. 325, 24–32 (2009).
Blair, E. et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215–1220 (2001).
Arad, M. et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109, 357–362 (2002).
Burwinkel, B. et al. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am. J. Hum. Genet. 76, 1034–1049 (2005).
Ozen, H. Glycogen storage diseases: new perspectives. World J. Gastroenterol. 13, 2541–2553 (2007).
Ayres, J.A. et al. DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue. Genomics 77, 18–26 (2001).
Davis, R.J., Harding, M., Moayedi, Y. & Mardon, G. Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis 46, 205–213 (2008).
Ikeda, K., Watanabe, Y., Ohto, H. & Kawakami, K. Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein. Mol. Cell. Biol. 22, 6759–6766 (2002).
Abdelhak, S. et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat. Genet. 15, 157–164 (1997).
Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).
Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).
Todd, J.A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).
Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).
Coresh, J. et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am. J. Kidney Dis. 39, 920–929 (2002).
Levey, A.S. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. 130, 461–470 (1999).
Stevens, L.A. et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am. J. Kidney Dis. 51, 395–406 (2008).
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39, S1–S266 (2002).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
R Development Core Team. R: a language and environment for statistical computing (The R Project for Statistical Computing, 2009). 〈http://www.R-project.org〉.
Gauderman, W.J. Sample size requirements for association studies of gene-gene interaction. Am. J. Epidemiol. 155, 478–484 (2002).
Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).
Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).
Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).
Bacanu, S.A., Devlin, B. & Roeder, K. The power of genomic control. Am. J. Hum. Genet. 66, 1933–1944 (2000).
Acknowledgements
We thank all participants and the study staff of the Age, Gene/Environment Susceptibility Reykjavik Study (AGES); the Amish Study; the Atherosclerosis Risk in Communities Study (ARIC); the Austrian Stroke Prevention study (ASPS); the Baltimore Longitudinal Study of Aging (BLSA); the Cardiovascular Health Study (CHS); the Erasmus Rucphen Family (ERF) study; the Family Heart Study (FamHS); the Framingham Heart Study (FHS); the Genetic Epidemiology Network of Atherosclerosis (GENOA); the Gutenberg Heart Study; the Health, Aging and Body Composition (HABC) study; the Health Professionals Follow-Up Study (HPFS); the Kooperative Gesundheitsforschung in der Region Augsburg (KORA); the Korcula Study; the Micros Study; the Nurses' Health Study (NHS); the Northern Swedish Population Health Study (NSPHS); the Orkney Complex Disease Study (Orcades); the PopGen Study; the Rotterdam Study (RS); the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA); the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR); the Study of Health in Pomerania (SHIP); the Sorbs Study; the Split Study; the Vis Study; and the Women's Genome Health Study (WGHS), as well as the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, for their invaluable contributions. A detailed list of acknowledgments and funding sources can be found in the Supplementary Note.
Author information
Authors and Affiliations
Contributions
Writing group: A.K., C.P., C.A.B., C.F., N.L.G., A.P., X.G., W.H.K., I.M.H., C.S.F.
Study design: L.J.L., T.B.H., V.G., A.P., E.B., J.C., A.K., L.F., J.M., N.L.G., T.L., D.S., B.M.P., M.G.S., B.A.O., C.M.v.D., I.B., M.P., C.S.F., Q.Y., S.K., M.d.A., E.J.A., Y.L., C.A.B., I.M.H., T.I., H.-E.W., N.K., C.M., I.R., P.P.P., F.B.H., G.C.C., U.G., J.F.W., S.H.W., A.F.W., H.C., A.H., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., K.E., H.V., P.K., A.T., M.B., W.W., O.P., N.H., C.H., V.V., D.I.C., G.P., A.N.P., P.M.R., S.B., T.F.M.
Study management: G.E., L.J.L., T.B.H., V.G., A.P., B.D.M., A.R.S., E.B., J.C., W.H.K., J.M., D.S., B.M.P., M.G.S., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., C.S.F., S.K., M.d.A., C.A.B., I.M.H., M.O., B.K., W.K., T.I., H.-E.W., C.M., I.R., L.Z., T.Z., C.P., C.F., P.P.P., M.C.C., F.B.H., G.C.C., A.J., G.Z., U.G., J.F.W., S.H.W., A.G.U., F.R., N.M.P.-H., M.I., T.R., B.K.K., L.K., B.P., F.K., R.R., K.E., H.V., M.S., A.T., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., S.B., A.N.P., P.M.R.
Subject recruitment: G.E., T.B.H., V.G., B.D.M., A.R.S., J.C., L.F., B.M.P., B.A.O., C.M.v.D., C.S.F., S.T.T., T.I., H.-E.W., I.R., L.Z., T.Z., I.K., P.P.P., A.J., J.F.W., S.H.W., S.S., A.D., J.C.W., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., H.V., A.T., M.B., O.P., C.H., S.B., T.Z., R.S.
Interpretation of results: T.B.H., A.P., E.B., J.C., W.H.K., A.K., L.F., T.T., F.G., N.L.G., T.L., T.H., B.M.P., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., X.G., C.S.F., Q.Y., S.-J.H., S.K., S.T.T., M.d.A., E.J.A., Y.L., T.S.L., C.A.B., I.M.H., M.O., B.K., W.K., I.R., T.Z., I.K., C.P., C.F., C.M., P.P.P., G.C.C., A.D.J., W.I., G.Z., U.G., J.F.W., S.H.W., A.D., Y.S.A., M.I., B.K., L.K., B.P., F.K., R.R., K.E., A.T., H.V., H.K.K., M.N., U.V., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., P.M.R.
Critical review of manuscript: All authors.
Statistical methods and analysis: A.V.S., T.A., V.G., J.R.O., E.R., A.K., M.L., R.S., H.S., T.T., N.L.G., T.L., B.M.P., A.I., X.G., M.F., C.S.F., Q.Y., S.J.H., S.K., M.d.A., E.J.A., K.L., Y.L., C.A.B., I.M.H., M.O., N.K., C.P., C.F., C.M., M.C.C., A.J., W.I., D.E., A.F., A.D., F.R., Y.S.A., N.M.P.-H., B.K., F.K., A.T., U.V., R.M., I.P., C.H., V.V., D.I.C., G.P., A.Z., A.B., S.W., J.F.F., D.E.A.
Genotyping: E.B., R.S., H.S., L.F., T.H., A.I., B.A.O., C.M.v.D., M.d.A., Y.L., T.I., H.-E.W., C.M., J.F.W., H.C., A.F., A.G.U., F.R., M.I., F.K., H.K.K., M.N., U.V., M.S., S.C., C.H., S.B., A.N.P., A.B., N.K.
Bioinformatics: A.V.S., T.A., J.R.O., M.S., M.C., T.T., A.I., B.A.O., C.M.v.D., Q.Y., A.D.J., E.J.A., Y.L., C.A.B., I.M.H., M.O., C.P., C.F., M.C.C., A.J., W.I., D.E., A.D., F.R., Y.S.A., F.K., A.T., H.K.K., U.V., D.I.C., G.P., D.E.A.
Corresponding authors
Ethics declarations
Competing interests
C.A.B. has received lecture fees from Novartis Deutschland GmbH, Fresenius Medical Care Deutschland GmbH and Sandoz Pharmaceuticals GmbH. S.B. and A.N.P. are employees of Amgen.
Supplementary information
Supplementary Text and Figures
Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1 and 2 (PDF 6057 kb)
Rights and permissions
About this article
Cite this article
Köttgen, A., Pattaro, C., Böger, C. et al. New loci associated with kidney function and chronic kidney disease. Nat Genet 42, 376–384 (2010). https://doi.org/10.1038/ng.568
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.568
This article is cited by
-
The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease
European Journal of Medical Research (2023)
-
Retinal determination gene networks: from biological functions to therapeutic strategies
Biomarker Research (2023)
-
Association between familial aggregation of chronic kidney disease and its incidence and progression
Scientific Reports (2023)
-
Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank
Nature Communications (2023)
-
The pathophysiology of distal renal tubular acidosis
Nature Reviews Nephrology (2023)