Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease
Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease
复制标题
DOI：
10.1016/j.ajhg.2017.05.004
复制
发表时间：
2017-06-01
影响因子：
9.8
通讯作者：
Susztak, Katalin
中科院分区：
文献类型：
--
作者：
Ko, Yi-An;Yi, Huiguang;Susztak, Katalin
慢性肾脏疾病（CKD）是一种复杂的基因-环境疾病，影响近10%的美国人口。全基因组关联研究（GWASs）已经确定了序列变异，定位于非编码基因组区域，与肾功能相关。尽管有这些强有力的观察结果，变异导致CKD的机制仍然是一个关键的未解之谜。表达数量性状位点（eQTL）分析是一种在特定组织类型中鉴定与基因表达变化相关的遗传变异的方法。我们假设结合CKD GWAS和肾脏eQTL结果的综合分析可以识别CKD的候选基因。我们将96份人类肾脏样本的基因型与rna -seq基因表达水平相关联，进行了eQTL分析。应用严格的统计标准，我们检测到1886个基因的表达随序列变异而不同。使用直接重叠和贝叶斯方法，我们确定了CKD的新的潜在靶基因。对于其中一个靶基因，溶酶体β A甘露糖苷酶（MANBA），我们观察到与肾脏中MANBA表达相关的遗传变异与CKD GWASs中鉴定的变异具有统计学意义的共定位，表明MANBA是CKD的潜在靶基因。具有危险等位基因的受试者肾脏中MANBA的表达明显降低。在斑马鱼中抑制manba表达导致肾小管缺陷和心包水肿，这些表型通常是由肾功能障碍引起的。我们的分析表明，由肾脏遗传变异驱动的基因表达变化可以突出CKD发展的潜在新靶基因。
Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.