1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
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DOI：
10.1038/srep45040
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发表时间：
2017-04-28
影响因子：
4.6
通讯作者：
Fuchsberger C
中科院分区：
文献类型：
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作者：
Gorski M;van der Most PJ;Teumer A;Chu AY;Li M;Mijatovic V;Nolte IM;Cocca M;Taliun D;Gomez F;Li Y;Tayo B;Tin A;Feitosa MF;Aspelund T;Attia J;Biffar R;Bochud M;Boerwinkle E;Borecki I;Bottinger EP;Chen MH;Chouraki V;Ciullo M;Coresh J;Cornelis MC;Curhan GC;d'Adamo AP;Dehghan A;Dengler L;Ding J;Eiriksdottir G;Endlich K;Enroth S;Esko T;Franco OH;Gasparini P;Gieger C;Girotto G;Gottesman O;Gudnason V;Gyllensten U;Hancock SJ;Harris TB;Helmer C;Höllerer S;Hofer E;Hofman A;Holliday EG;Homuth G;Hu FB;Huth C;Hutri-Kähönen N;Hwang SJ;Imboden M;Johansson Å;Kähönen M;König W;Kramer H;Krämer BK;Kumar A;Kutalik Z;Lambert JC;Launer LJ;Lehtimäki T;de Borst M;Navis G;Swertz M;Liu Y;Lohman K;Loos RJF;Lu Y;Lyytikäinen LP;McEvoy MA;Meisinger C;Meitinger T;Metspalu A;Metzger M;Mihailov E;Mitchell P;Nauck M;Oldehinkel AJ;Olden M;Wjh Penninx B;Pistis G;Pramstaller PP;Probst-Hensch N;Raitakari OT;Rettig R;Ridker PM;Rivadeneira F;Robino A;Rosas SE;Ruderfer D;Ruggiero D;Saba Y;Sala C;Schmidt H;Schmidt R;Scott RJ;Sedaghat S;Smith AV;Sorice R;Stengel B;Stracke S;Strauch K;Toniolo D;Uitterlinden AG;Ulivi S;Viikari JS;Völker U;Vollenweider P;Völzke H;Vuckovic D;Waldenberger M;Jin Wang J;Yang Q;Chasman DI;Tromp G;Snieder H;Heid IM;Fox CS;Köttgen A;Pattaro C;Böger CA;Fuchsberger C
HapMap imputed全基因组关联研究（GWAS）已经揭示了bbbb50个位点，其中具有小等位基因频率b>5%的常见变异与肾功能相关。GWAS使用更完整的参考集进行代入，例如来自1000基因组计划的参考集，有望识别出以前的工作所遗漏的新位点。为了研究这样一个更完整的变异目录的价值，我们对110,517名欧洲血统参与者进行了一项基于肾小球滤过率（eGFR）的GWAS荟萃分析，使用1000个基因组输入的数据。我们发现了10个新的基因座，其p值< 5 × 10−8，之前基于hapmap的GWAS遗漏了这些基因座。其中6个位点（HOXD8、ARL15、PIK3R1、EYA4、ASTN2和EPB41L3）被1000个基因组参考面板中特有的共同snp标记。通过通路分析，我们发现了39个显著（FDR < 0.05）基因和127个显著（FDR < 0.05）富集的基因集，这是我们之前的分析所遗漏的。其中，鉴定出的10个新基因是肾脏发育、碳水化合物代谢、心间隔发育和葡萄糖代谢途径的一部分。这些结果强调了在全基因组测序在大样本中变得可行之前，从更密集的参考面板重新输入的效用。
HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.