Ko Yi-An, Yi Huiguang, Qiu Chengxiang, Huang Shizheng, Park Jihwan, Ledo Nora, Köttgen Anna, Li Hongzhe, Rader Daniel J, Pack Michael A, Brown Christopher D, Susztak Katalin
Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute of Genetic Epidemiology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
Am J Hum Genet. 2017 Jun 1;100(6):940-953. doi: 10.1016/j.ajhg.2017.05.004.
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.
慢性肾脏病（CKD）是一种复杂的基因 - 环境疾病，影响着近10%的美国人口。全基因组关联研究（GWAS）已经确定了定位于非编码基因组区域的序列变异，这些变异与肾功能相关。尽管有这些确凿的观察结果，但变异导致CKD的机制仍然是一个关键的未解决问题。表达数量性状位点（eQTL）分析是一种识别与特定组织类型中基因表达变化相关的遗传变异的方法。我们假设，将CKD的GWAS和肾脏eQTL结果进行综合分析可以识别出CKD的候选基因。我们通过将96个人类肾脏样本中的基因型与基于RNA测序的基因表达水平进行关联，进行了eQTL分析。应用严格的统计标准，我们检测到1886个基因，其表达因序列变异而不同。使用直接重叠和贝叶斯方法，我们确定了CKD的新潜在靶基因。关于其中一个靶基因，溶酶体β - 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的GWAS中鉴定出的变异在统计学上具有显著的共定位，表明MANBA是CKD的一个潜在靶基因。具有风险等位基因的受试者的肾脏中MANBA的表达显著降低。在斑马鱼中抑制manba表达会导致肾小管缺陷和心包水肿，这些是通常由肾功能障碍引起的表型。我们的分析表明，肾脏中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。
