Association Analysis Identifies a Susceptibility Locus on Chromosome 3q27 for Primary Angle Closure Glaucoma

Abstract

Purpose: : To identify susceptibility genes for primary angle closure glaucoma (PACG) through analysis of quantitative trait loci (QTL) identified for one of its major anatomical risk factors, anterior chamber depth (ACD).

Methods: : We conducted a population-based genome-wide association study (GWAS) of ACD in Singaporean Malays, Indians and Beijing Chinese aged between 40-80 years from three well characterized population-based studies: the Singapore Malay Eye Study (SiMES), the Singapore Indian Eye Study (SINDI) and Beijing Eye Study (BES), respectively. ACD was measured using the IOLMaster. Genotyping was performed with Illumina Human610K Quad BeadChips. QTLs identified for ACD were tested in 825 PACG cases and 917 controls of Singaporean Chinese ethnicity. Replication was performed in two additional sample collections from Beijing (988 cases and 1,656 controls) and Hong Kong (246 cases and 225 controls). In the replication stage, SNPs were genotyped with the Sequenom MassArray platform. Sample collections used for association analysis for the quantitative endophenotype, ACD were independent and distinct from those used for association analysis for disease (PACG).

Results: : Meta-analysis of ACD data in the three sample collections (SiMES, N = 1752; SINDI, N = 1860; and BES1, N = 872) revealed two strongly associated intragenic SNPs on chromosome 3q27.1 showing P < 5 x 10^-7 (SNP1 and SNP2; pair-wise LD comparison: D’ = 1.0, r² = 1.0). We genotyped the lead SNP (SNP1) via direct sequencing in a further 824 samples from the Beijing Eye Study (BES2). Combined analysis of all the sample collections genotyped for SNP1 (overall N = 5,308) showed genome-wide significant association with ACD (Pmeta = 8.17 x 10^-9, βmeta = -0.045 per-copy of the minor allele). However, we did not observe significant association between SNP1 and axial length in individuals of Chinese descent. We also observed genome wide significant association between this marker and increased risk of primary angle closure glaucoma on meta-analysis of data from all patient samples (N = 2,059 cases and N = 2,798 controls; unguided genotype test; P = 2.78 x 10^-10, dominant odds ratio (OR) = 1.42).

Conclusions: : We have identified a common intragenic variant on chromosome 3q27.1 as being associated with PACG, likely mediated by shallower anterior chamber but not overall eyeball length. This study also confirms the validity of using quantitative endophenotypes in gene discovery for diagnostically heterogeneous disorders.

Keywords: gene mapping • anterior segment • genetics