A catalog of genetic loci associated with kidney function from analyses of a million individuals
A catalog of genetic loci associated with kidney function from analyses of a million individuals
复制标题
DOI：
10.1038/s41588-019-0407-x
复制
发表时间：
2019-06-01
期刊：
影响因子：
30.8
通讯作者：
Pattaro, Cristian
中科院分区：
文献类型：
--
作者：
Wuttke, Matthias;Li, Yong;Pattaro, Cristian
慢性肾脏疾病（CKD）是一种多系统并发症的公共卫生负担。通过对估计肾小球滤过率（eGFR）和独立复制的全基因组关联研究（n = 1,046,070）的跨祖先荟萃分析，我们确定了264个相关位点（166个新位点）。其中，147种可能与肾功能相关，基于与替代肾功能标志物血尿素氮的关联（n = 416,178）。途径和富集分析，包括具有肾脏表型的小鼠模型，支持肾脏作为主要靶器官。在452264名独立个体中，较低eGFR的遗传风险评分与临床诊断的CKD相关。对783978名欧洲血统个体的eGFR相关性和46个人体组织（包括肾小管间质和肾小球肾室）的基因表达进行共定位分析，发现17个基因在肾脏中存在差异表达。精细定位突出了11个基因的错义驱动变体和肾脏特异性调节变体。这些结果为转化研究提供了一个全面的分子靶点优先列表。
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.