Genome-wide association analyses identify novel gene associated with central corneal thickness and keratoconus; The Nagahama Study

Abstract

Purpose : Keratoconus is a common ocular disorder resulting in progressive corneal thinning, and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is an inherited characteristic, and associated with keratoconus. In the present study, we performed genome-wide association study for CCT and identified the novel susceptibility locus associated with CCT and keratoconus development.

Methods : In this analysis, we enrolled 6,931 Japanese individuals from Nagahama Study (3,830 for the discovery stage and 3,101 for the replication stage). Association analyses were performed using linear regression model, for the average of CCT in both eyes, adjusting for age, gender and the average of axial length in both eyes. Fixed effect meta-analysis was then performed with 2 population-based studies, including 2,622 Malay from Singapore Malay Eye Study and 877 Chinese from Singapore Chinese Eye Study. We recruited keartoconus patients from the Tokyo Dental University Hospital (N = 179), and compared to healthy Japanese controls. Genome-wide genotyping was performed using Illumina Human610-Quad, CoreExome24, HumanExome or HumanOmni2.5M arrays. Genotype imputation was performed using the 1000 Genomes Project as the reference panel.

Results : During the first stage, we identified a genome-wide significant association of rs599xxxxx (In gene, P_discovery = 3.27 × 10^-11). As TaqMan probe for rs599xxxxx could not be designed, we analyzed rs23xxxxx which showed the second strongest association with CCT (P_discovery = 4.17× 10^-11) in the following replication stage. This SNP showed significant association with CCT (P_replication = 4.58 × 10^-4). We further conducted trans-ethnic replication analyses using 2 other cohorts of 2 different ethnicities. In both cohorts, rs23xxxxx C allele showed the CCT-increasing effect, and meta-analysis of all data revealed strong association between rs23xxxxx and CCT (P_meta-all = 8.08×10^-14). Next, we conducted association analysis using 179 keratoconus cases and 9994 Japanese healthy controls, which revealed rs23xxxxx was also associated with the development of keratoconus (P = 0.038).

Conclusions : We identified the novel susceptibility locus of rs23xxxxx associated with CCT and keratoconus development.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.