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. The online version of this article (10.1186/s13040-018-0179-3) contains supplementary material, which is available to authorized users.

中央角膜厚度（CCT）的遗传结构远未被了解。大多数与CCT相关的变异位于非编码区域，这增加了后续功能特性研究的难度。因此，对CCT相关位点进行综合功能分析，通过确定位于CCT遗传网络中心的关键基因，可能有助于克服这些问题。 对所有已报道的CCT全基因组关联研究（GWAS）主要单核苷酸多态性（SNP）及其代理变异进行了包括功能注释、富集分析和蛋白质 - 蛋白质相互作用分析在内的综合分析。功能注释由CADD、GWAVA和Eigen进行。使用ToppGene套件对CCT相关基因进行富集分析。通过GeneMANIA进行蛋白质 - 蛋白质相互作用网络和基因共表达分析。 功能注释确定了8个基因（ADAMSTS6、ARID5B、FOXO1、AKAP13、COL4A3、COL8A2、TBL1XR1和KCMB2）具有优先性，这些基因包含的SNP具有很强的调控潜力证据。还表明CCT相关基因在胶原蛋白相关通路和圆锥角膜表型中显著富集，并且其中一些基因被发现参与一个相互作用网络。 这项研究揭示了位于CCT遗传网络中心的关键基因，并为CCT GWAS研究结果背后的遗传调控提供了新的见解。 本文的在线版本（10.1186/s13040 - 018 - 0179 - 3）包含补充材料，授权用户可获取。