Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Ko, Y.A., Yi, H., Qiu, C., Huang, S., Park, J., Ledo, N., Köttgen, A., Li, H., Rader, D.J., Pack, M.A., Brown, C.D., Susztak, K.
American journal of human genetics   100: 940-953 (Journal)
Registered Authors
Brown, Christopher, Pack, Michael
CKD, GWAS, eQTL, gene network, gene regulation, kidney
MeSH Terms
  • Animals
  • Base Sequence
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Gene Regulatory Networks
  • Genetic Variation*
  • Genome-Wide Association Study
  • Humans
  • Kidney/metabolism
  • Kidney/pathology
  • Kidney Diseases/genetics*
  • Kidney Diseases/pathology
  • Linkage Disequilibrium/genetics
  • Polymorphism, Single Nucleotide/genetics
  • Quantitative Trait Loci/genetics
  • Quantitative Trait, Heritable
  • Reproducibility of Results
  • Zebrafish/genetics
  • beta-Mannosidase/genetics
28575649 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes