Quantitative Trait Locus Analysis of SIX1-SIX6 With Retinal Nerve Fiber Layer Thickness in Individuals of European Descent

Abstract

Purpose To perform a quantitative trait locus (QTL) analysis and evaluate whether a locus between SIX1 and SIX6 is associated with retinal nerve fiber layer (RNFL) thickness in individuals of European descent. Design Observational, multi-center, cross-sectional study. Methods 231 participants were recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Association of rs10483727 in SIX1-SIX6 with global and sectoral RNFL thickness was performed. Quantitative trait analysis with the additive model of inheritance was analyzed using linear regression. Trend analysis was performed to evaluate the mean global and sectoral RNFL thickness with 3 genotypes of interest (T/T, C/T, C/C). All models were adjusted for age and gender. Results Direction of association between T allele and RNFL thickness was consistent in the global and different sectoral RNFL regions. Each copy of the T risk allele in rs10483727 was associated with −0.16 μm thinner global RNFL thickness (β=−0.16, 95% CI: −0.28 to −0.03; P=0.01). Similar patterns were found for the sectoral regions, including inferior (P=0.03), inferior-nasal (P=0.017), superior-nasal (P=0.0025), superior (P=0.002) and superior-temporal (P=0.008). The greatest differences were observed in the superior and inferior quadrants, supporting clinical observations for RNFL thinning in glaucoma. Thinner global RNFL was found in subjects with T/T genotypes compared to subjects with C/T and C/C genotypes (P=0.044). Conclusions Each copy of the T risk allele has an additive effect and was associated with thinner global and sectoral RNFL. Findings from this QTL analysis further support a genetic contribution to glaucoma pathophysiology.

Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study

“…These results were consistent with previous candidate SNP evaluations on rs33912345 30–32 . In addition, our findings suggest that the 32-sector region-based approach for cpRNFLT enables the detection of underpowered and undermined genetic associations in 4-sector analyses.…”

“…This is the only locus where an association with cpRNFLT has been established 30–32 . In this study, our detailed analysis further specified the cpRNFL region of association, and revealed that SIX1/SIX6 affects cpRNFL thinning at 281.3–303.8° among the inferior region, which may have clinical and biological relevance since retinal nerve fibre layer defects also occur in this region.…”

“…To date, three studies have reported significant associations of SIX1/SIX6 polymorphisms to cpRNFL thinning in the upper and lower sectors—but not the nasal and temporal sectors—in 30 POAG cases 32 , 1,243 population controls 31 , and 231 other participants consisting of 20% normal, 44% of suspected glaucoma, and 36% confirmed glaucoma cases 30 . In contrast, our analyses used 2,306 population controls and showed that rs33912345 had the strongest association with cpRNFLT at 292.5–303.8° and a marginal association at 78.8–90.0°.…”

“…To date, genetic studies on cpRNFLT have shown consistent contributions of the single nucleotide polymorphisms (SNPs) rs33912345 and rs10483727 located within the SIX1/SIX6 loci to cpRNFL thinning in the superior and inferior sectors, but not in the temporal, nasal, and global sectors 30–32 . The significance of the SIX1/SIX6 locus in glaucoma was initially discovered by GWAS for VCDR and primary open-angle glaucoma (POAG), and subsequent studies confirmed the association of polymorphisms in this region with glaucoma onset.…”

Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population

“…Several subsequent studies have also confirmed that the SIX1/SIX6 locus was significantly correlated with POAG and VCDR in different independent ethnic cohorts (Burdon et al, 2015;Chen et al, 2015;Fan et al, 2011;Iglesias et al, 2014;Mabuchi et al, 2015;Osman et al, 2012b;Philomenadin et al, 2015;Ramdas et al, 2011;Wiggs et al, 2012), but the association has not yet been demonstrated in African cohorts owing to the high frequency of the risk allele both in patients and controls (Liu et al, 2013;Williams et al, 2015). Recently, two population-based studies using cohorts from Singapore and of European-descents showed that both glaucomatous and nonglaucomatous subjects with risk allele variants in the SIX1/SIX6 locus (rs10483727 and rs33912345) were susceptible to thinner retinal nerve fiber layer thickness, which confirmed the results of previous studies (Carnes et al, 2014;Cheng et al, 2015;Kuo et al, 2015). Our results that both rs33912345 and rs10483727 were strongly associated with NTG and POAG were consistent with the findings of a previous association study also based on the Chinese population (Chen et al, 2015).…”