Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
Nat Genet. 2024 Oct;56(10):2078-2092. doi: 10.1038/s41588-024-01904-6. Epub 2024 Sep 10.
Kidney failure, the decrease of kidney function below a threshold necessary to support life, is a major cause of morbidity and mortality. We performed a genome-wide association study (GWAS) of 406,504 individuals in the UK Biobank, identifying 430 loci affecting kidney function in middle-aged adults. To investigate the cell types affected by these loci, we integrated the GWAS with human kidney candidate cis-regulatory elements (cCREs) identified using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). Overall, 56% of kidney function heritability localized to kidney tubule epithelial cCREs and an additional 7% to kidney podocyte cCREs. Thus, most heritable differences in adult kidney function are a result of altered gene expression in these two cell types. Using enhancer assays, allele-specific scATAC-seq and machine learning, we found that many kidney function variants alter tubule epithelial cCRE chromatin accessibility and function. Using CRISPRi, we determined which genes some of these cCREs regulate, implicating NDRG1, CCNB1 and STC1 in human kidney function.
肾衰竭，即肾脏功能下降到不足以维持生命的程度，是发病率和死亡率的主要原因。我们对英国生物库中的 406504 人进行了全基因组关联研究（GWAS），确定了 430 个影响中年人肾功能的基因座。为了研究这些基因座影响的细胞类型，我们将 GWAS 与使用单细胞转座酶可及染色质测序（scATAC-seq）鉴定的人类肾脏候选顺式调控元件（cCREs）进行了整合。总体而言，56%的肾功能遗传率定位于肾脏肾小管上皮细胞 cCREs，另外 7%定位于肾脏足细胞 cCREs。因此，成人肾功能的大多数可遗传差异是这两种细胞类型中基因表达改变的结果。通过增强子测定、等位基因特异性 scATAC-seq 和机器学习，我们发现许多肾功能变异改变了肾小管上皮细胞 cCRE 的染色质可及性和功能。使用 CRISPRi，我们确定了其中一些 cCRE 调控的基因，表明 NDRG1、CCNB1 和 STC1 与人类肾功能有关。
