Genome-wide association study and meta-analysis of intraocular pressure

Ozel, Ayse Bilge; Moroi, Sayoko E.; Reed, David; Nika, Melisa; Schmidt, Caroline M.; Akbari, Sara; Scott, Kathleen M.; Rozsa, Frank W.; Pawar, Hemant; Musch, David C.; Lichter, Paul R.; Gaasterland, Doug; Branham, Kari; Gilbert, Jesse; Garnai, Sarah J.; Chen, Wei; Othman, Mohammad; Heckenlively, John R.; Swaroop, Anand; Abecasis, Gonçalo R.; Friedman, David S.; Zack, Donald J.; Ashley-Koch, Allison E.; Ulmer, Megan; Kang, Jae H.; Liu, Yutao; Yaspan, Brian L.; Haines, Jonathan L.; Allingham, R. Rand; Hauser, Michael A.; Pasquale, Louis R.; Wiggs, Janey L.; Richards, Julia E.; Li, Jun Z.

doi:10.1007/s00439-013-1349-5

Cited by 92 publications

(70 citation statements)

References 49 publications

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“…17, 51 Consequently, we considered that the association between TMCO1 and glaucoma might be influenced by IOP. However, TMCO1 remains associated with POAG in the OHTS cohort even when baseline IOP is controlled using linear regression.…”

Section: Discussionmentioning

confidence: 99%

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study

et al. 2016

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Purpose Primary open angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. Here we measure the relative risk for glaucoma these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS). Design Comparative Series Participants 1057 (65%) of the 1636 participants of the OHTS were enrolled in this genetics ancillary study. Methods DNA samples were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using ANOVA. The two largest subgroups non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%) were also analyzed separately. The probability of developing glaucoma over the course of the OHTS was compared between participants stratified for TMCO1 risk alleles using Kaplan-Meier and Cox proportional hazards analyses. Main Outcome Measures Association of POAG with known genetic factors. Results No association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls (p = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of developing glaucoma than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increase relative risk comparable to that of some previously analyzed clinical measures (i.e. intraocular pressure). Conclusions The size of the OHTS cohort and its composition of two large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase risk for developing glaucoma among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that have long been associated with glaucoma.

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Section: Discussionmentioning

confidence: 99%

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study

et al. 2016

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“…27,28 A recent publication describes the criteria for inclusion and exclusion for GLAUGEN, 23 and the details are also available at dbGaP, accession number phs000308.v1.p1. The NEIGHBOR study included 2132 POAG cases and 2290 controls from 12 institutions and also provided data for genetic investigations of central corneal thickness, 29,30 IOP, 31 and POAG. 28 The descriptive information about the design, inclusion/ exclusion criteria, study sites, and collected data in the NEIGHBOR study was recently published.…”

Section: Study Populationmentioning

confidence: 99%

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

Kang

Loomis

Yaspan³

et al. 2014

Eye

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“…Gene association studies have reproducibly associated polymorphisms at CAV1/2 gene loci with both POAG and IOP101112131415161718. However, functional role(s) that caveolins/caveolae play in IOP maintenance are incompletely understood.…”

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confidence: 99%

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

Elliott

Ashpole

et al. 2016

Sci Rep

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Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1−/−) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm’s canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1−/− outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1−/− eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.

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Genome-wide association study and meta-analysis of intraocular pressure

Cited by 92 publications

References 49 publications

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

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