Association of Glaucoma Risk Variants with Retinal Nerve Fiber Layer Thickness: The Singapore Epidemiology of Eye Diseases (SEED) Study

Abstract

Purpose : Recent genome-wide association studies (GWAS) have identified several genes associated with glaucoma, but their role in its pathogenesis is unclear. This study aims to investigate the association between identified glaucoma risk genes and parapapillary retinal nerve fiber layer (pRNFL) thickness.

Methods : A cross-sectional study was conducted with subjects from the three major ethnic groups – Malay, Indian and Chinese – in Singapore. Subjects underwent ocular examinations and pRNFL thickness was measured using spectral-domain optical coherence tomography (SD-OCT). 28 glaucoma-associated SNPs from 14 loci were identified from previous GWAS. Multivariable linear regression with additive genetic model was performed to evaluate the association between the risk variants and pRNFL adjusted for age, sex, genetic principal component and axial length.

Results : 7,125 eyes from 3,877 subjects were included for analysis. Among the risk genes, only SIX6 was associated with reduction in pRNFL thickness. Within SIX6, 4 SNPs were associated with reduction of average pRNFL thickness, including rs33912345 (β= -1.09, p = 1.5 x 10^-5), rs10483727 (β= -1.01, p = 6.1 x 10^-5), rs34935520 (β= -0.99, p = 1.1 x 10^-4) and rs4436712 (β= -1.00, p = 1.2 x 10^-4). The association of rs33912345, the most significant SIX6 SNP, with RNFL thickness was strongest in Chinese (β= -1.19, p = 7.2 x 10^-3), followed by Indian (β= -0.91, p = 0.014) and Malay (β= -1.22, p = 0.025) population. All of the SIX6 risk alleles were also significantly associated with reduction in superior and inferior quadrant of RNFL (P< 0.001). No other glaucoma risk SNPs was associated with RNFL thickness after Bonferroni correction.

Conclusions : Although the significant SIX6 risk variants were in high linkage disequilibrium (R² > 0.8), they were reported to be associated with different glaucoma traits. Our study further showed that several SIX6 risk variants were associated with reduction in RNFL thickness. The effects of other glaucoma risk SNPs on RNFL thickness appear to be weak.

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