Identifying pathological myopia associated genes with GenePlexus in protein-protein interaction network

Abstract

Introduction: Pathological myopia, a severe form of myopia, is characterized by an extreme elongation of the eyeball, leading to various vision-threatening complications. It is broadly classified into two primary types: high myopia, which primarily involves an excessive axial length of the eye with potential for reversible vision loss, and degenerative myopia, associated with progressive and irreversible retinal damage.

Methods: Leveraging data from DisGeNET, reporting 184 genes linked to high myopia and 39 genes associated with degenerative myopia, we employed the GenePlexus methodology in conjunction with screening tests to further explore the genetic landscape of pathological myopia.

Results and discussion: Our comprehensive analysis resulted in the discovery of 21 new genes associated with degenerative myopia and 133 genes linked to high myopia with significant confidence. Among these findings, genes such as ADCY4, a regulator of the cAMP pathway, were functionally linked to high myopia, while THBS1, involved in collagen degradation, was closely associated with the pathophysiology of degenerative myopia. These previously unreported genes play crucial roles in the underlying mechanisms of pathological myopia, thereby emphasizing the complexity and multifactorial nature of this condition. The importance of our study resides in the uncovering of new genetic associations with pathological myopia, the provision of potential biomarkers for early screening, and the identification of therapeutic targets.

Keywords: DisGeNET; GenePlexus; degenerative myopia; disease gene; high myopia; pathological myopia.

FIGURE 1

Flowchart depicting the procedure of extracting genes linked to pathological myopia. Initially, we gathered validated genes associated with high myopia and degenerative myopia from the DisGeNET database. Following this, we constructed a PPI network using data from the STRING database, a crucial step in visualizing the complex interplay between proteins. The GenePlexus tool was then utilized on this gene network to highlight candidates with a high likelihood of relevance. Subsequent refinement of these potential candidates was conducted through a series of three distinct screening tests, aiming to distill the list to a final set of genes deemed most pertinent. The culmination of our process involved a detailed evaluation of the relationship between these inferred genes and pathological myopia, employing a literature-based analysis to substantiate their relevance to the disease.

FIGURE 2

Bar plot illustrating the frequency of interactions between predicted proteins and known proteins linked to high myopia and degenerative myopia with high confidence scores. Among the recently discovered genes associated with high myopia and degenerative myopia, almost all have at least one interaction with known disease-related genes in the PPI network, indicating a strong connection between these inferred proteins and pathological myopia.

FIGURE 3

Venn plot of pathological myopia-related genes identified based on the RWR method and those identified based on GenePlexus.

FIGURE 4

Enrichment analysis results of identified genes related to degenerative myopia. (A) Enriched gene ontology (GO) terms; (B) Enriched pathways. BP, biological process; CC, cellular component; MF, molecular function.

FIGURE 5

Enrichment analysis results of identified genes related to high myopia. (A) Enriched gene ontology (GO) terms; (B) Enriched pathways. BP, biological process; CC, cellular component; MF, molecular function.