We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10-10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Ains-The age-related changes in the biochemical composition of the collagenous matrix of the human lamina cribrosa were investigated. Methods-An age range (3 weeks to 92 years old) of human laminae cribrosae, dissected free of any surrounding structures which contained collagen, were analysed for collagen solubility (n= 58) total collagen content (n=46), proportion of collagen types (n=38), and collagen cross linking (n=30), using hydroxyproline analysis, scanning densitometry of peptides after cyanogen bromide digestion, and high performance liquid chromatography, respectively. Results-Age-related changes included an increase in total collagen and a decrease in the proportion of type III collagen within the lamina cribrosa. The collagen cross link pyridinoline was present at low levels, but demonstrated no trend with age. An age-related increase was found in pentosidine, an advanced glycation product. Conclusion-These changes in collagen composition imply that the mechanical properties of the lamina cribrosa are altered, resulting in a stiffer, less resilient structure with age. Such alterations in structure may contribute to the increased susceptibility of the elderly to axonal damage in chronic open angle glaucoma. (Br_7 Ophthalmol 1995; 79: 368-375)

Aims-To investigate changes in the mechanical compliance of ex vivo human lamina cribrosa with age. Methods-A laser scanning confocal microscope was used to image the surface of the fluorescently labelled lamina cribrosa in cadaver eyes. A method was developed to determine changes in the volume and strain of the lamina cribrosa created by increases in pressure. The ability of the lamina cribrosa to reverse its deformation on removal of pressure was also measured. Results-Volume and strain measurements both demonstrated that the lamina cribrosa increased in stiVness with age and the level of pressure applied. The ability of the lamina cribrosa to regain its original shape and size on removal of pressure appeared to decrease with age, demonstrating an age related decrease in resilience of the lamina cribrosa. Conclusions-The mechanical compliance of the human lamina cribrosa decreased with age. Misalignment of compliant cribriform plates in a young eye may exert a lesser stress on nerve axons, than that exerted by the rigid plates of an elderly lamina cribrosa. The resilience of the lamina cribrosa also decreased with age, suggesting an increased susceptibility to plastic flow and permanent deformation. Such changes may be of importance in the explanation of age related optic neuropathy in primary open angle glaucoma. (Br J Ophthalmol 2000;84:318-323) The lamina cribrosa is a lattice-like structure, consisting of successive perforated cribriform plates across the optic nerve canal, through which pass bundles of nerve fibres. The plates are lined by basement membranes and their cores are filled with significant amounts of fibrillar collagens and elastic fibres. During ageing, the constituents of these cribriform plates are altered. [1][2][3][4] It is likely that such changes will alter the mechanical behaviour of the ageing lamina cribrosa and therefore compromise its ability to support the nerve axons that pass through it.The distribution of axonal loss in early glaucoma appears to be related to regional diVerences in architecture of the lamina cribrosa. The superior and inferior regions of the lamina cribrosa, which exhibit greater pore size and less dense connective tissue, are thought to be more susceptible to axonal damage.5 6 The arcuate retinal ganglion cell axons, which pass through these regions, are damaged first in early glaucoma.The cause of glaucomatous axonal damage is unknown; ischaemia and mechanical damage as a result of a raised intraocular pressure or rearrangement of the cribriform plates are among the theories that have been proposed. [7][8][9] Whatever the cause, compression of the lamina cribrosa appears to occur before detectable glaucomatous field loss. 10Age related changes in the lamina cribrosa include increases in the amounts of collagen types I, III, and IV 3 4 within the cribriform plates, which lead to an overall increase in total collagen content. [1][2][3] We have also demonstrated alterations in the ratio of collagen types I and III and an increase in non-enzymatic glyc...

Aims/Background-The morphological changes in Bruch's membrane and its constituent collagen seen Conclusion-Changes in the constituentcollagens may contribute to the accumulation ofdebris in Bruch's membrane with age and interfere with the function of the retinal pigment epithelium, with subsequent consequences for the overlying photoreceptors. (Br_J Ophthalmol 1995; 79: 944-952) The high incidence of age-related macular degeneration (ARMD) and its significant impact on the visual function in the elderly population has led to considerable interest in the function and relations of the photoreceptors, the retinal pigment epithelium (RPE), and its adjacent structures, in particular Bruch's membrane. Their failure to function normally is critical in the pathological process that leads to the development of ARMD, and the changes that occur in these tissues with age and in the disease process are of relevance to our understanding of ARMD.In aging and ARMD considerable morphological changes are seen in Bruch's membrane. Changes include the deposition of material between the RPE and its basement membrane. Drusen, which are focal, lie between the RPE basement membrane and the inner collagenous zone of Bruch's membrane. 1-3 More diffuse changes are also seen, with the deposition of debris, vesicular material, and membrane coated bodies within Bruch's membrane, especially in the inner collagenous zone.4 This material has a high lipid content but its composition appears to vary between individuals.5 It is believed to originate in the photoreceptor outer segments and to be the product of RPE metabolism.69 Although the morphological changes that occur in aging and their nature are well described, the mechanism by which the material is retained in the matrix of the membrane is not understood, nor are the consequences of this deposition process. 10The structure of Bruch's membrane depends on the integrity of collagen fibres and concurrent with the macroscopic changes there appear to be age-related changes in the nature of the collagen. There is an increased number of striated collagen fibres present in both the inner and outer collagenous layers with increasing age. This 64 nm banded material is assumed to be the fibrillar type I collagen. This is accompanied by the deposition of short segments of a 100 nm banded form which is assumed to be collagen type VI.2 8 11 The distribution of the collagen types in Bruch's membrane has been studied with immunohistochemical techniques12 13 which demonstrated the presence of types I, III, IV, and V collagen. The staining for types IV and V appeared to be bilaminar, below the RPE and around the choriocapillaris, while that for types I and III tended to be diffuse throughout the thickness of the membrane. In older tissue there appeared to be increased immunostaining for type I collagen as well as frequent interruptions in the bilaminar staining pattern for types IV and V collagen. Significantly, these interruptions were not always associated with drusen.12 Electron microscopic s...