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New loci associated with kidney function and chronic kidney disease

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.

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Figure 1: Genome-wide −log10 P value plot from stage 1.
Figure 2: Comparison of magnitude of association with eGFR estimated from serum creatinine (eGFRcrea) and cystatin c (eGFRcys) for SNPs identified in stage 1 discovery analyses.
Figure 3: Distribution of the genetic risk score in the discovery samples and relation of risk score categories to mean eGFRcrea and prevalence of CKD.

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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.

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Authors

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

Correspondence to Daniel I Chasman, W H Kao, Iris M Heid or Caroline S Fox.

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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.

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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

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