Functional relevance for central cornea thickness-associated genetic variants by using integrative analyses.

Background: The genetic architecture underlying central cornea thickness (CCT) is far from understood. Most of the CCT-associated variants are located in the non-coding regions, raising the difficulty of following functional characterizations. Thus, integrative functional analyses on CCT-associated loci might benefit in overcoming these issues by prioritizing the hub genes that are located in the center of CCT genetic network.

Methods: Integrative analyses including functional annotations, enrichment analysis, and protein-protein interaction analyses were performed on all reported CCT GWAS lead SNPs, together with their proxy variants. Functional annotations were conducted by CADD, GWAVA, and Eigen. Enrichment analyses for CCT-associated genes were performed using ToppGene suite. Protein-protein interaction network and gene co-expression analyses were performed by GeneMANIA.

Results: Functional annotations prioritized eight genes ( ADAMSTS6, ARID5B, FOXO1, AKAP13, COL4A3, COL8A2, TBL1XR1, and KCMB2 ) harboring SNPs with strong evidence of regulatory potential. It was also shown that CCT-associated genes were significantly enriched in collagen-related pathways and the phenotype of keratoconus, and some of them were found to be involved in one interaction network.

Conclusion: This study revealed the hub genes that were located in the center of CCT genetic network and provided a new insight into the genetic regulation underlying CCT GWAS findings.