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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).

Glaucoma is a term describing a group of ocular disorders with multi-factorial etiology united by a clinically characteristic intraocular pressure-associated optic neuropathy. It is not a single entity and is sometimes referred to in the plural as the glaucomas. All forms are potentially progressive and can lead to blindness. The diverse conditions that comprise glaucoma are united by a clinically characteristic optic neuropathy: glaucomatous optic neuropathy (GON). Evidence suggests that the primary site of neurological injury is at the optic nerve head. This fact enables the conditions to be grouped, irrespective of the causal mechanism(s). The term experimental glaucoma implies model resemblance to the human condition. We propose that 'experimental glaucoma' be restricted to animal models with demonstrable features of GON and/or evidence of a primary axonopathy at the optic nerve head. A fundamental inadequacy in this framework is any reference to the pathogenesis of GON, which remains unclear.

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The present data may have implications for the study of the pathology associated with the visual pathway in diseases such as glaucoma.

Investigators using cells designated as RGC-5 should confirm the species to be of rat origin and retinal-specific marker expression before considering their use as retinal ganglion-like cells.

Retinitis pigmentosa (RP) is an inherited condition that features degeneration of rod and cone photoreceptors. In all forms of RP, the genetic mutation is expressed exclusively in rods; however, cones die too. The secondary death of cones in RP remains somewhat mysterious. A better understanding of the mechanisms that cause cone degeneration in RP could lead to novel treatments that preserve cones. There are a number of prevailing theories that attempt to explain cone degeneration in RP. One concept is that cone survival is dependent on trophic factors produced by rods. Another hypothesis is that cones suffer from a nutrient shortage after rods have been lost. Additionally, oxidative stress and pro-inflammatory microglial activation have also been suggested to play a role in cone death. The present review evaluates the evidence supporting these theories and provides an update on the mechanisms of cone degeneration in RP.

The neurodegenerative disease glaucoma is characterised by the progressive death of retinal ganglion cells (RGCs) and structural damage to the optic nerve (ON). New insights have been gained into the pathogenesis of glaucoma through the use of rodent models; however, a coherent picture of the early pathology remains elusive. Here, we use a validated, experimentally induced rat glaucoma model to address fundamental issues relating to the spatio-temporal pattern of RGC injury. The earliest indication of RGC damage was accumulation of proteins, transported by orthograde fast axonal transport within axons in the optic nerve head (ONH), which occurred as soon as 8 h after induction of glaucoma and was maximal by 24 h. Axonal cytoskeletal abnormalities were first observed in the ONH at 24 h. In contrast to the ONH, no axonal cytoskeletal damage was detected in the entire myelinated ON and tract until 3 days, with progressively greater damage at later time points. Likewise, down-regulation of RGC-specific mRNAs, which are sensitive indicators of RGC viability, occurred subsequent to axonal changes at the ONH and later than in retinas subjected to NMDA-induced somatic excitotoxicity. After 1 week, surviving, but injured, RGCs had initiated a regenerative-like response, as delineated by Gap43 immunolabelling, in a response similar to that seen after ON crush. The data presented here provide robust support for the hypothesis that the ONH is the pivotal site of RGC injury following moderate elevation of IOP, with the resulting anterograde degeneration of axons and retrograde injury and death of somas.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-011-0807-1) contains supplementary material, which is available to authorized users.