Fine mapping of the RXRA-COL5A1 locus for central corneal thickness

Abstract

Purpose: Central corneal thickness (CCT) is associated with vision disorders including glaucoma and keratoconus. Multiple studies have reported the association of the RXRA-COL5A1 locus on chromosome 9 with CCT. Here we describe in silico fine mapping, followed by expression analysis.

Methods: We conducted this research using current GWAS data from the Los Angeles Latino Eye Study (n = 1,800). All Latino subjects were age 40 years and older. We carried out regional genotype imputation over the RXRA-COL5A1 locus based on the 1000 Genomes Project reference panels and retained only SNPs of high imputation quality with MACH Rsq greater than 0.80. We performed single-marker and conditional analyses with adjustment for age, sex and principal components of genetic ancestry. We also performed expression analysis using human ocular tissues.

Results: We replicated several previously reported SNPs within the RXRA-COL5A1 region and discovered a novel SNP, rs3118515 (P = 8.25E-10) in the uncharacterized LOC100506532 (gene type: miscRNA), that better captures the association with CCT in Latinos. Conditional analysis demonstrated that rs3118515 is responsible for the association of the RXRA-COL5A1 locus. Multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human cornea.

Conclusions: Fine mapping and expression analysis improved the localization and the annotation of SNPs that regulate CCT at the RXRA-COL5A1 locus, indicating the involvement of LOC100506532 and offering insights in the molecular mechanism of CCT.

Keywords: 480 cornea: basic science • 539 genetics • 534 gene mapping