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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Lookup NU author(s): Professor Paul Burton

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Abstract

© 2016, Nature Publishing Group. All rights reserved. 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.


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Author(s): Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, Garnaas M, Tin A, Sorice R, Li Y, Taliun D, Olden M, Foster M, Yang Q, Chen M-H, Pers TH, Johnson AD, Ko Y-A, Fuchsberger C, Tayo B, Nalls M, Feitosa MF, Isaacs A, Dehghan A, D'Adamo P, Adeyemo A, Dieffenbach AK, Zonderman AB, Nolte IM, Van Der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Dreisbach AW, Franke A, Uitterlinden AG, Metspalu A, Tonjes A, Lupo A, Robino A, Johansson A, Demirkan A, Kollerits B, Freedman BI, Ponte B, Oostra BA, Paulweber B, Kramer BK, Mitchell BD, Buckley BM, Peralta CA, Hayward C, Helmer C, Rotimi CN, Shaffer CM, Muller C, Sala C, Van Duijn CM, Saint-Pierre A, Ackermann D, Shriner D, Ruggiero D, Toniolo D, Lu Y, Cusi D, Czamara D, Ellinghaus D, Siscovick DS, Ruderfer D, Gieger C, Grallert H, Rochtchina E, Atkinson EJ, Holliday EG, Boerwinkle E, Salvi E, Bottinger EP, Murgia F, Rivadeneira F, Ernst F, Kronenberg F, Hu FB, Navis GJ, Curhan GC, Ehret GB, Homuth G, Coassin S, Thun G-A, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Jacobs G, Li G, Wichmann H-E, Campbell H, Schmidt H, Wallaschofski H, Volzke H, Brenner H, Kroemer HK, Kramer H, Lin H, Leach IM, Ford I, Guessous I, Rudan I, Prokopenko I, Borecki I, Heid IM, Kolcic I, Persico I, Jukema JW, Wilson JF, Felix JF, Divers J, Lambert J-C, Stafford JM, Gaspoz J-M, Smith JA, Faul JD, Wang JJ, Ding J, Hirschhorn JN, Attia J, Whitfield JB, Chalmers J, Viikari J, Coresh J, Denny JC, Karjalainen J, Fernandes JK, Endlich K, Butterbach K, Keene KL, Lohman K, Portas L, Launer LJ, Lyytikainen L-P, Yengo L, Franke L, Ferrucci L, Rose LM, Kedenko L, Rao M, Struchalin M, Kleber ME, Cavalieri M, Haun M, Cornelis MC, Ciullo M, Pirastu M, De Andrade M, McEvoy MA, Woodward M, Adam M, Cocca M, Nauck M, Imboden M, Waldenberger M, Pruijm M, Metzger M, Stumvoll M, Evans MK, Sale MM, Kahonen M, Boban M, Bochud M, Rheinberger M, Verweij N, Bouatia-Naji N, Martin NG, Hastie N, Probst-Hensch N, Soranzo N, Devuyst O, Raitakari O, Gottesman O, Franco OH, Polasek O, Gasparini P, Munroe PB, Ridker PM, Mitchell P, Muntner P, Meisinger C, Smit JH, Abecasis GR, Adair LS, Alexander M, Altshuler D, Amin N, Arking DE, Arora P, Aulchenko Y, Bakker SJL, Bandinelli S, Barroso I, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Bis JC, Boehnke M, Bonnycastle LL, Bornstein SR, Bots ML, Bragg-Gresham JL, Brand S-M, Brand E, Braund PS, Brown MJ, Burton PR, Casas JP, Caulfield MJ, Chakravarti A, Chambers JC, Chandak GR, Chang Y-PC, Charchar FJ, Chaturvedi N, Cho YS, Clarke R, Collins FS, Collins R, Connell JM, Cooper JA, Cooper MN, Cooper RS, Corsi AM, Dorr M, Dahgam S, Danesh J, Smith GD, Day INM, Deloukas P, Denniff M, Dominiczak AF, Dong Y, Doumatey A, Elliott P, Elosua R, Erdmann J, Eyheramendy S, Farrall M, Fava C, Forrester T, Fowkes FGR, Fox ER, Frayling TM, Galan P, Ganesh SK, Garcia M, Gaunt TR, Glazer NL, Go MJ, Goel A, Grassler J, Grobbee DE, Groop L, Guarrera S, Guo X, Hadley D, Hamsten A, Han 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Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Online publication date: 21/01/2016

Acceptance date: 27/10/2015

ISSN (print): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms10023

DOI: 10.1038/ncomms10023

PubMed id: 26831199


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