9 In addition, variation at TMCO1 has been associated with intraocular pressure, 16 while 9p21 and SIX1/SIX6 are associated with cup-to-disc ratio 17 in normal individuals. We provide evidence for association at SIX1/SIX6, 9p21, and nominally at TMCO1 with incident OAG. Thus, loci associated with advanced glaucoma and relevant biometric traits are also associated with the initial onset of OAG (incidence). Those SNPs discovered in previous cohorts with typical (nonadvanced) OAG are not found to be associated with AUY-922 molecular weight OAG
incidence in our cohort, although power to detect weaker associations or those at rarer SNPs is limited. The association of sex with incident OAG in the cohort has been previously reported, 11 as has the higher-than-expected level of hypertension in the BMES cohort. 18 and 19 The current cohort was sufficiently ZD1839 powered to detect an odds ratio of ∼1.6. This is larger than those observed in the original discovery cohorts of cross-sectional (prevalent OAG) patient recruitment, although significant effects were still observed in this study, suggesting that the SNPs may be more important in predicting disease onset than progression, or that the true effect size is larger than previously
reported. However, larger prospective cohorts will be needed to properly assess the 8q22 and CAV1/CAV2 loci in particular. A nominal association was observed at TMCO1. This SNP has a lower allele frequency than others in the study (11% in controls) and the finding did not reach significance here in the context of multiple testing, owing to the lower power of this study (∼36%) to detect an effect at the minor allele frequency of 11%. We have previously reported an association of this locus with prevalent OAG in the BMES cohort with odds ratio (OR) = PAK6 1.57, P = .022. 7 The odds ratio for incident OAG reported in the current study was larger (OR = 1.74, P = .013) despite the smaller sample size. We thus conclude that TMCO1 is also confirmed to be associated
with incident OAG. The current study shows that OAG loci that are associated with OAG-relevant ocular parameters (cup-to-disc ratio and intraocular pressure) are specifically associated with OAG incidence independently of other known risk factors. This suggests that these loci are responsible at least in part for the initiation of OAG, consistent with their role in determination of these risk factor traits, which are themselves predictive for OAG development. We show also that the loci specifically associated with advanced glaucoma may also be important in initiation of OAG, and thus could be important in risk stratification among glaucoma suspect and early glaucoma patients.