Investigating a downstream gene of Gpnmb using the systems genetics method

Mol Vis. 2019 Apr 23:25:222-236. eCollection 2019.

Abstract

Purpose: Glaucoma is characterized by optic nerve damage and retinal ganglion cell loss. The glycoprotein neuromedin B-associated (Gpnmb) gene is well-known to be involved in the glaucoma disease process. The purpose of this study is to identify a downstream gene through which Gpnmb affects the glaucoma phenotypes using a systems genetics approach.

Methods: Retinal gene expression data for the BXD recombinant inbred (RI) strains (n=75) have previously been generated in our laboratory for a glaucoma study, and these data were used for genetic and bioinformatics analysis. Expression quantitative trait locus (eQTL) mapping and genetic correlation methods were used to identify a gene downstream of Gpnmb. Gene-set enrichment analysis was used to evaluate gene function and to construct coexpression networks.

Results: The level of Gpnmb expression is associated with a highly statistically significant cis-eQTL. Stanniocalcin 1 (Stc1) has a significant trans-eQTL mapping to the Gpnmb locus. The expression of Gpnmb and Stc1 is highly correlated in the retina and other tissues, as well as with glaucoma-related phenotypes. Gene Ontology and pathway analysis showed that Stc1 and its covariates are highly associated with apoptosis, oxidative stress, and mitochondrial activity. A generated gene network indicated that Gpnmb and Stc1 are directly connected to and interact with other genes with similar biologic functions.

Conclusions: These results suggest that Stc1 may be a downstream candidate of Gpnmb, and that both genes interact with other genes in a network to develop glaucoma pathogenesis through mechanisms such as apoptosis and oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Computational Biology / methods
  • Disease Models, Animal
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Ontology
  • Gene Regulatory Networks*
  • Glaucoma / genetics*
  • Glaucoma / metabolism
  • Glaucoma / pathology
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Humans
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Molecular Sequence Annotation
  • Oxidative Stress
  • Phenotype
  • Protein Interaction Mapping
  • Quantitative Trait Loci
  • Signal Transduction

Substances

  • Eye Proteins
  • Glycoproteins
  • Gpnmb protein, mouse
  • Membrane Glycoproteins
  • teleocalcin