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Nat Commun. 2016 Jan 21;7:10023. doi: 10.1038/ncomms10023.

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

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 MH, Pers TH, Johnson AD, Ko YA, 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 Å, Demirkan A, Kollerits B, Freedman BI, Ponte B, Oostra BA, Paulweber B, Krämer BK, Mitchell BD, Buckley BM, Peralta CA, Hayward C, Helmer C, Rotimi CN, Shaffer CM, Müller 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 GA, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Jacobs G, Li G, Wichmann HE, Campbell H, Schmidt H, Wallaschofski H, Völzke 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 JC, Stafford JM, Gaspoz JM, 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, Lyytikäinen LP, 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, Kähönen 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; ICBP Consortium; AGEN Consortium; CARDIOGRAM; CHARGe-Heart Failure Group; ECHOGen Consortium, Kovacs P, Wild PS, Froguel P, Rettig R, Mägi R, Biffar R, Schmidt R, Middelberg RP, Carroll RJ, Penninx BW, Scott RJ, Katz R, Sedaghat S, Wild SH, Kardia SL, Ulivi S, Hwang SJ, Enroth S, Kloiber S, Trompet S, Stengel B, Hancock SJ, Turner ST, Rosas SE, Stracke S, Harris TB, Zeller T, Zemunik T, Lehtimäki T, Illig T, Aspelund T, Nikopensius T, Esko T, Tanaka T, Gyllensten U, Völker U, Emilsson V, Vitart V, Aalto V, Gudnason V, Chouraki V, Chen WM, Igl W, März W, Koenig W, Lieb W, Loos RJ, Liu Y, Snieder H, Pramstaller PP, Parsa A, O'Connell JR, Susztak K, Hamet P, Tremblay J, de Boer IH, Böger CA, Goessling W, Chasman DI, Köttgen A, Kao WH, Fox CS.

Collaborators (446)

Abecasis GR, Adair LS, Alexander M, Altshuler D, Amin N, Arking DE, Arora P, Aulchenko Y, Bakker SJ, 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 SM, Brand E, Braund PS, Brown MJ, Burton PR, Casas JP, Caulfield MJ, Chakravarti A, Chambers JC, Chandak GR, Chang YP, Charchar FJ, Chaturvedi N, Shin Cho Y, Clarke R, Collins FS, Collins R, Connell JM, Cooper JA, Cooper MN, Cooper RS, Corsi AM, Dörr M, Dahgam S, Danesh J, Davey Smith G, Day IN, 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 FG, Fox ER, Frayling TM, Galan P, Ganesh SK, Garcia M, Gaunt TR, Glazer NL, Go MJ, Goel A, Grässler J, Grobbee DE, Groop L, Guarrera S, Guo X, Hadley D, Hamsten A, Han BG, Hardy R, Hartikainen AL, Heath S, Heckbert SR, Hedblad B, Hercberg S, Hernandez D, Hicks AA, Hilton G, Hingorani AD, Bolton JA, Hopewell JC, Howard P, Humphries SE, Hunt SC, Hveem K, Ikram MA, Islam M, Iwai N, Jarvelin MR, Jackson AU, Jafar TH, Janipalli CS, Johnson T, Kathiresan S, Khaw KT, Kim HL, Kinra S, Kita Y, Kivimaki M, Kooner JS, Kumar MJ, Kuh D, Kulkarni SR, Kumari M, Kuusisto J, Kuznetsova T, Laakso M, Laan M, Laitinen J, Lakatta EG, Langefeld CD, Larson MG, Lathrop M, Lawlor DA, Lawrence RW, Lee JY, Lee NR, Levy D, Li Y, Longstreth WT, Luan J, Lucas G, Ludwig B, Mangino M, Mani KR, Marmot MG, Mattace-Raso FU, Matullo G, McArdle WL, McKenzie CA, Meitinger T, Melander O, Meneton P, Meschia JF, Miki T, Milaneschi Y, Mohlke KL, Mooser V, Morken MA, Morris RW, Mosley TH, Najjar S, Narisu N, Newton-Cheh C, Nguyen KD, Nilsson P, Nyberg F, O'Donnell CJ, Ogihara T, Ohkubo T, Okamura T, Ong RT, Ongen H, Onland-Moret NC, O'Reilly PF, Org E, Orru M, Palmas W, Palmen J, Palmer LJ, Palmer ND, Parker AN, Peden JF, Peltonen L, Perola M, Pihur V, Platou CG, Plump A, Prabhakaran D, Psaty BM, Raffel LJ, Rao DC, Rasheed A, Ricceri F, Rice KM, Rosengren A, Rotter JI, Rudock ME, Sõber S, Salako T, Saleheen D, Salomaa V, Samani NJ, Schwartz SM, Schwarz PE, Scott LJ, Scott J, Scuteri A, Sehmi JS, Seielstad M, Seshadri S, Sharma P, Shaw-Hawkins S, Shi G, Shrine NR, Sijbrands EJ, Sim X, Singleton A, Sjögren M, Smith NL, Soler Artigas M, Spector TD, Staessen JA, Stancakova A, Steinle NI, Strachan DP, Stringham HM, Sun YV, Swift AJ, Tabara Y, Tai ES, Talmud PJ, Taylor A, Terzic J, Thelle DS, Tobin MD, Tomaszewski M, Tripathy V, Tuomilehto J, Tzoulaki I, Uda M, Ueshima H, Uiterwaal CS, Umemura S, van der Harst P, van der Schouw YT, van Gilst WH, Vartiainen E, Vasan RS, Veldre G, Verwoert GC, Viigimaa M, Vinay DG, Vineis P, Voight BF, Vollenweider P, Wagenknecht LE, Wain LV, Wang X, Wang TJ, Wareham NJ, Watkins H, Weder AB, Whincup PH, Wiggins KL, Witteman JC, Wong A, Wu Y, Yajnik CS, Yao J, Young JH, Zelenika D, Zhai G, Zhang W, Zhang F, Zhao JH, Zhu H, Zhu X, Zitting P, Zukowska-Szczechowska E, Okada Y, Wu JY, Gu D, Takeuchi F, Takahashi A, Maeda S, Tsunoda T, Chen P, Lim SC, Wong TY, Liu J, Young TL, Aung T, Teo YY, Kim YJ, Kang D, Chen CH, Tsai FJ, Chang LC, Fann SJ, Mei H, Hixson JE, Chen S, Katsuya T, Isono M, Albrecht E, Yamamoto K, Kubo M, Nakamura Y, Kamatani N, Kato N, He J, Chen YT, Tanaka T, Reilly MP, Schunkert H, Assimes TL, Hall A, Hengstenberg C, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Wells GA, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Schnabel R, Sinning C, Lackner KJ, Tiret L, Nicaud V, Cambien F, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel TF, Barbalic M, Chen IY, Demissie-Banjaw S, Folsom A, Lumley T, Marciante K, Taylor KD, Volcik K, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Linsel-Nitschke P, Stark K, Schreiber S, Aherrahrou Z, Bruse P, Doering A, Klopp N, Diemert P, Loley C, Medack A, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Epstein SE, Rader DJ, Nelson CP, Wright BJ, Balmforth AJ, Ball SG, Loehr LR, Rosamond WD, Benjamin E, Haritunians T, Couper D, Murabito J, Wang YA, Stricker BH, Chang PP, Willerson JT, Felix SB, Watzinger N, Aragam J, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett DK, Gottdiener JS, Blettner M, Friedrich N.

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.

PMID:
26831199
PMCID:
PMC4735748
DOI:
10.1038/ncomms10023
[Indexed for MEDLINE]
Free PMC Article

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