Collagen-related genes influence the glaucoma risk factor, central corneal thickness

Abstract

Central corneal thickness (CCT) is a risk factor of glaucoma, the most common cause of irreversible blindness worldwide. The identification of genetic determinants affecting CCT in the normal population will provide insights into the mechanisms underlying the association between CCT and glaucoma, as well as the pathogenesis of glaucoma itself. We conducted two genome-wide association studies for CCT in 5080 individuals drawn from two ethnic populations in Singapore (2538 Indian and 2542 Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067, p(meta) = 5.40 × 10⁻¹³, interval of RXRA-COL5A1 rs1536478, p(meta) = 3.05 × 10⁻⁹). We confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469) [rs9938149 (p(meta) = 1.63 × 10⁻¹⁶) and rs12447690 (p(meta) = 1.92 × 10⁻¹⁴)]. Evidence of association exceeding the formal threshold for genome-wide significance was observed at rs7044529, an SNP located within COL5A1 when data from this study (n = 5080, P = 0.0012) were considered together with all published data (reflecting an additional 7349 individuals, p(Fisher) = 1.5 × 10⁻⁹). These findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma.

Genetic Covariance Between Central Corneal Thickness and Anterior Chamber Volume: A Hungarian Twin Study

“…Vitart et al (2010) reported 3 new loci associated with CCT (COL5A1, AKAP13, and AVGR8). Vithana et al (2011) also identified novel genetic loci associated with CCT (COL8A2), and confirmed the involvement of a previously reported gene for CCT (ZNF469). Their findings implicate the involvement of collagen genes.…”

Primary open-angle glaucoma genes

“…[85][86][87] A segment of chromosome 16q near the gene ZNF469 was identified as an important quantitative traits locus for CCT in all three studies. ZNF469 is an excellent candidate for regulating CCT as mutations in this gene were previously linked with brittle cornea syndrome (BCS OMIM #229200).…”

“…88 The specific variant in ZNF469 that influences corneal thickness has not been identified; however, it has been estimated that it may be responsible for 1.29% of CCT variance. Other genetic factors that influence CCT [85][86][87] have been discovered, including variants in collagen genes (COL5A1 and COL8A2). Detection of the first genetic factors for CCT is a significant advance and has paved the way for more discoveries.…”

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…Vithana et al 139 conducted two GWAS for CCT in 5080 individuals drawn from two ethnic populations in Singapore (Indian and Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067 and interval of RXRA-COL5A1 rs1536478). They confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469 rs9938149 and rs12447690), and they showed an association exceeding the formal threshold for genome-wide significance of COL5A1 rs7044529 and CCT.…”

“…Their findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma. 139 Khor et al 140 conducted a GWAS on 4445 Singaporean individuals with replication in Rotterdam, the Netherlands, on 9326 individuals of Caucasian ancestry, using the most widely reported parameter for optic disc traits, the optic disc area. They identified a novel locus on chromosome 22q13.1, CARD10, which strongly associates with optic disc area in both Singaporean cohorts 140 The results of quantitative trait analysis can complement the findings from GWAS; for example, Rotimi et al 87 in 2006 suggested a locus on 5q22 was linked to high IOP and this lies within the WDR36 gene, which is implicated in POAG.…”