Multiple Differentially Methylated Regions Specific to Keratoconus Explain Known Keratoconus Linkage Loci

Area of Science:

• Ophthalmology
• Genetics
• Epigenetics

Background:

• Keratoconus (KTCN) is a complex eye disorder impacting visual function.
• Its etiology involves genetic and environmental factors, with a suspected role for epigenetic modifications.

Purpose of the Study:

• To investigate the role of epigenetic factors, particularly DNA methylation, in the development of keratoconus.
• To identify specific differentially methylated regions in KTCN corneas.

Main Methods:

• Reduced representation bisulfite sequencing was employed on human corneal samples from KTCN and non-KTCN individuals.
• RNA sequencing data from previous studies were reanalyzed to correlate gene expression with methylation patterns.

Main Results:

• Multiple KTCN-specific differentially methylated regions were identified, many overlapping known KTCN linkage loci and associated chromosome arms.
• DNA methylation changes in WNT3 and WNT5A were observed, potentially explaining Wnt signaling pathway dysregulation in KTCN.
• Overlap was found between differentially methylated regions and genes with altered expression in KTCN.

Conclusions:

• This study provides the first analysis of DNA methylation changes in human KTCN corneas.
• Identified genomic regions with distinct methylation patterns correlate with KTCN susceptibility loci and transcriptomic alterations.
• Epigenetic dysregulation, especially involving the Wnt signaling pathway, is implicated in keratoconus pathogenesis.