Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Abstract

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

The pathogenesis of keratoconus

“…The authors concluded that these findings demonstrated that part of the genetic predisposition to KC is mediated through genes underlying CCT, with the remaining predisposition attributable to alternative mechanisms. 91 This conclusion mirrors the clinical finding that the occurrence of a relatively thin cornea in isolation is distinct from the progressive regional thinning of the cornea that is a feature of KC.…”

“…This study identified 16 new loci associated with CCT at genome-wide significance. 91 To investigate whether any CCT-associated loci identified also influence genetic susceptibility to KC, the authors tested for association of these loci in a case-control study including 874 patients with KC. This meta-analysis identified six SNPs that were strongly associated with a risk of KC, within or nearby the following genes/loci; FOXO1, FNDC3B, RXRA-COL5A1, MPDZ-NF1B, COL5A1, and ZNF469.…”

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

“…27,28 A recent publication describes the criteria for inclusion and exclusion for GLAUGEN, 23 and the details are also available at dbGaP, accession number phs000308.v1.p1. The NEIGHBOR study included 2132 POAG cases and 2290 controls from 12 institutions and also provided data for genetic investigations of central corneal thickness, 29,30 IOP, 31 and POAG. 28 The descriptive information about the design, inclusion/ exclusion criteria, study sites, and collected data in the NEIGHBOR study was recently published.…”

Common and Rare Genetic Risk Factors for Glaucoma

“…A recent study from the International Glaucoma Genetics Consortium (IGGC) identified 16 loci significantly associated with CCT ( Fig. 3) (Lu et al 2013). Pathway analyses suggested that collagen and extracellular matrix pathways are important regulators of CCT (Lu et al 2013).…”

“…Additionally, genetic variants associated with quantitative ocular traits that are risk factors for common forms of glaucoma have also been identified. These include IOP (van Koolwijk et al 2012), central corneal thickness (CCT) (Vithana et al 2011;Lu et al 2013), and optic nerve parameters including cup-to-disc ratio and optic nerve area (Ramdas et al 2010;Macgregor et al 2010;Axenovich et al 2011) (Table 3). The clinical features of POAG generally include both elevated IOP and optic nerve degeneration.…”