Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.
Nature communications 2015 ; 7: 10023.
Pattaro C, Teumer A, Gorski M, Chu AY, Mijatovic V, Sorice R, Olden M, Yang Q, Chen MH, Pers TH, Johnson AD, Fuchsberger C, Nalls M, Feitosa MF, Isaacs A, Dehghan A, Dieffenbach AK, Zonderman AB, Nolte IM, van der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Franke A, Uitterlinden AG, Metspalu A, Tönjes A, Robino A, Johansson Å, Demirkan A, Freedman BI, Oostra BA, Mitchell BD, Buckley BM, Hayward C, Rotimi CN, Shaffer CM, Sala C, van Duijn CM, Shriner D, Ruggiero D, Toniolo D, Cusi D, Siscovick DS, Ruderfer D, Gieger C, Grallert H, Holliday EG, Boerwinkle E, Salvi E, Bottinger EP, Rivadeneira F, Kronenberg F, Ehret GB, Homuth G, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Wichmann HE, Campbell H, Schmidt H, Wallaschofski H, Völzke H, Brenner H, Leach IM, Ford I, Rudan I, Prokopenko I, Heid IM, Kolcic I, Jukema JW, Wilson JF, Felix JF, Smith JA, Faul JD, Wang JJ, Ding J, Hirschhorn JN, Attia J, Whitfield JB, Viikari J, Coresh J, Denny JC, Karjalainen J, Butterbach K, Lohman K, Portas L, Launer LJ, Lyytikäinen LP, Yengo L, Franke L, Ferrucci L, Rose LM, Kleber ME, Cornelis MC, Ciullo M, Pirastu M, Woodward M, Cocca M, Imboden M, Waldenberger M, Stumvoll M, Evans MK, Kähönen M, Bochud M, Rheinberger M, Verweij N, Bouatia-Naji N, Martin NG, Hastie N, Soranzo N, Raitakari O, Gottesman O, Franco OH, Polasek O, Gasparini P, Munroe PB, Ridker PM, Mitchell P, Meisinger C, Smit JH, Kovacs P, Wild PS, Froguel P, Rettig R, Mägi R, Biffar R, Schmidt R, Middelberg RP, Penninx BW, Scott RJ, Wild SH, Kardia SL, Ulivi S, Enroth S, Trompet S, Turner ST, Harris TB, Zeller T, Zemunik T, Lehtimäki T, Illig T, Esko T, Tanaka T, Gyllensten U, Völker U, Vitart V, Gudnason V, März W, Koenig W, Lieb W, Loos RJ, Snieder H, Pramstaller PP, Parsa A, O'Connell JR, Böger CA, Chasman DI, Kao WH, Fox CS
DOI : 10.1038/ncomms10023
PubMed ID : 26831199
PMCID : PMC4735748
Abstract
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.