Common genetic variants associated with open-angle glaucoma

Abstract

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

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

“…The SIX1-SIX6 locus was first identified as being associated with increased VCDR, which is considered as one of critical ocular biomarkers for the diagnosis of glaucoma and its progression to blindness (Ramdas et al, 2010). 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).…”

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

“…Recently, several POAG susceptibility loci were identified by genome-wide association (GWA) studies [16][17][18][19][20] and were replicated in multiple ethnicities: 7q31.2 between CAV1 and CAV2, 16,21 9p21.3 with CDKN2B-AS1, 19,20,[22][23][24][25][26] 10q21.3 with ATOH7, 17,18,22,27 and 14q23.1 between SIX1 and SIX6. 17,20,22,28 One of the GWA studies demonstrated the association of POAG with six SNPs that flanked the ZP4, PLXDC2, and TMTC2 genes located at chromosome loci 1q43, 10p12.31, and 12q21.31, respectively, in a Japanese population; 29 however, these associations were not replicated in a South Indian, 30 Afro-Caribbean, 24 or Chinese 31 population.…”

“…17,20,22,28 One of the GWA studies demonstrated the association of POAG with six SNPs that flanked the ZP4, PLXDC2, and TMTC2 genes located at chromosome loci 1q43, 10p12.31, and 12q21.31, respectively, in a Japanese population; 29 however, these associations were not replicated in a South Indian, 30 Afro-Caribbean, 24 or Chinese 31 population. These conflicting results can be ascribed to factors such as a small sample size with inadequate statistical power, different phenotype definitions, population-specific linkage disequilibrium (LD), effect-size bias, or population stratification.…”

Genome-wide association studies: applications and insights gained in Ophthalmology

“…98 The most common condition related to optic disc parameters is of course glaucoma. Ramdas et al 99 performed a meta-analysis, investigating SNPs found to be related to optic disc parameters in populations of POAG upon whom GWAS have been completed. Of particular interest, they confirmed three loci associated with optic disc parameters also having an association with POAG.…”