Understanding the role of corneal biomechanics-associated genetic variants by bioinformatic analyses

• Published in: International ophthalmology Vol. 42; no. 3; pp. 981 - 988
• Main Authors: Sun, Xiao, Gao, Xiang, Mu, Bo-kun, Wang, Yan
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.03.2022; Springer Nature B.V
• Subjects: Annotations; Biological activity; Biomechanical engineering; Biomechanical Phenomena; Biomechanics; Cbfa-1 protein; Collagen; Collagen (type I); Computational Biology; Cornea; Corneal dystrophy; Dystrophy; Extracellular matrix; Eye diseases; Gene mapping; Genes; Genetic analysis; Genetic diversity; Genetic variance; Genome-Wide Association Study; Humans; Keratoconus; Mechanical properties; Medicine; Medicine & Public Health; Nucleotides; Ophthalmology; Original Paper; Phenotypes; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Resistance factors; Single-nucleotide polymorphism; Smad3 protein; Bioinformatic analysis; Corneal biomechanical properties; GWAS; SNP
• ISSN: 0165-5701; 1573-2630
• DOI: 10.1007/s10792-021-02081-9

Purpose To analyze functions of corneal biomechanical properties (CBP)-related variants as corneal resistance factor (CRF) and corneal hysteresis (CH). Methods Related single nucleotide polymorphisms (SNPs) and genes were identified from NHGRI-EBI GWAS catalog, GWASdb v2 and possible data in published studies. HaploReg v4.1 was used to find linkage SNPs. Functional annotations were performed by GWAVA, CADD and RegulomeDB. GTEx Portal database was used to find out expression quantitative trait locus (eQTL) association. Enrichr was used to annotate the function of GWAS gene and the associated signal pathway. STING (v11.0) database was utilized for protein interaction and network construction. Results The integration of 302 CH-associated and 420 CRF-associated lead SNPs has produced 531 CBP-associated lead SNPs. A total of 5,324 proxy variants identified using the HaploReg v4.1 and lead SNPs were functionally annotated. Based on the threshold (CADD ≥ 10, GWAVA ≥ 0.4 and RegulomeDB < rank 3), 23 prioritized putative regulatory SNPs were identified. Eight prioritized eQTL variants (rs75203695, rs34861673, rs846766, rs11024102, rs1377416, rs3829492, rs9934438 and rs197912) were found with strong potential of CBP regulation. It was indicated that CBP-associated genes were significantly enriched in extracellular matrix receptor interaction pathway, closely related to the phenotype of corneal dystrophy and keratoconus. COL1A1, SMAD3, BMP4 and RUNX2 occupied the core position in the co-expression network. Conclusions Data integrative analysis can evaluate CBP variations and explore collagen and extracellular matrix pathways in CBP regulation, which is a promising tool to investigate biological process of corneal diseases.