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

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.

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.

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.

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.