A genome-wide association study (GWAS) for open angle glaucoma (OAG) blindness was conducted using a discovery cohort of 590 cases with severe visual field loss and 3956 controls. Genome-wide significant associations were identified at TMCO1 (rs4656461 (G) OR=1.68, p=6.1x10 -10 ) and CDKN2B-AS1 (rs4977756 (A) OR = 1.50, p=4.7x10 -9 ). These findings were replicated in a second cohort of advanced OAG cases (rs4656461 p=0.010; rs4977756 p=0.042) and two further cohorts of less severe OAG. The study wide odds ratios are 1.51 (1.35-1.68), p=6.00x10 -14 at TMCO1, and 1.39 (1.28-1.51), p=1.35x10 -14 at CDKN2B-AS1 (also known as CDKN2BAS and ANRIL). Carriers of 1 or more risk alleles at both loci concurrently are at >3-fold increased risk of glaucoma. We demonstrate retinal expression of genes at both loci, and show that CDKN2A and CDKN2B are strongly upregulated in an animal model of glaucoma.Glaucoma is a group of neurodegenerative ocular diseases united by a clinically characteristic optic neuropathy. It is the second leading cause of blindness worldwide 1 . Primary open angle glaucoma (OAG) is the commonest subtype 1 . OAG pathogenesis and factors determining disease progression are poorly understood. Early intervention with measures to reduce intraocular pressure retards visual loss in most individuals 2 , but many cases of glaucoma remain undiagnosed until irreversible vision loss has occurred. Elucidation of SNPs associated with severe outcomes could enable better targeting of treatments which carry cost and morbidity, to individuals at highest risk of blindness. Linkage and candidate gene studies have identified several genes likely to be involved in OAG including myocilin 3 and NTF4 4 , although for the latter, findings have varied in different populations 5 . A recent GWAS using Icelandic OAG cases of unselected severity identified association with variants near CAV1 6 . To identify genes predisposing individuals to OAG blindness, we performed a GWAS in Australian Caucasians with advanced OAG (individuals with OAG who have progressed to severe visual field loss or blindness).
Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide. Both IOP and POAG are highly heritable. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578) that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 advanced POAG cases and 1,992 controls. Association of the top SNPs from the discovery stage was investigated in two Australian replication cohorts (total 932 cases, 6,862 controls) and two US replication cohorts (total 2,616 cases, 2,634 controls). Meta-analysis of all cohorts revealed three novel loci associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493 [G] OR=1.31, P= 2.1 × 10-19), within AFAP1 (rs4619890 [G] OR=1.20, P= 7.0 × 10-10) and within GMDS (rs11969985 [G] OR=1.31, and P= 7.7 × 10-10). Using RT-PCR and immunolabelling, we also showed that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
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