Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.
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DOI：
10.1038/ncomms10023
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发表时间：
2016-01-21
影响因子：
16.6
通讯作者：
Fox CS
中科院分区：
文献类型：
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作者：
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
肾小球滤过率降低定义为慢性肾脏疾病，并与心血管和全因死亡率相关。我们对估计肾小球滤过率（eGFR）的全基因组关联研究进行了荟萃分析，结合了133，413名个体的数据，并在多达42，166名个体中进行了重复。我们确定了24个新的和确认29个以前确定的位点。在这53个基因座中，19个与糖尿病个体的eGFR相关。利用生物信息学，我们发现，在eGFR基因座的基因是丰富的表达在肾脏组织和相关的肾脏发育和跨膜转运蛋白活性，肾脏结构，和葡萄糖代谢的调节途径。染色质状态映射和DNA酶I超敏性分析在成人组织中显示相关变体优先映射到肾脏而不是肾外组织中的调节区域。这些发现表明，eGFR的遗传决定因素主要通过肾脏内的直接作用介导，并突出了重要的细胞类型和生物学途径。 肾小球滤过率（eGFR）降低是慢性肾脏疾病的标志。在这里，Pattaro等人进行了一项荟萃分析，以发现与eGFR变异相关的几个新基因座，并发现与eGFR基因座相关的基因通常编码与肾脏发育潜在相关的蛋白质。
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. Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.