Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Objective Conventional optic disc margin-based neuroretinal rim measurements lack a solid anatomical and geometrical basis. An optical coherence tomography (OCT) index, Bruch’s membrane opening minimum rim width (BMO-MRW), addresses these deficiencies and has higher diagnostic accuracy for glaucoma. We characterized BMO-MRW and peripapillary retinal nerve fiber layer thickness (RNFLT) in a normal population. Design Multi-centred cross-sectional study. Participants Normal White subjects. Methods Approximately equal number of subjects in each decade group (20–90 years) was enrolled in 5 centers. Subjects had normal ocular and visual field examinations. We obtained OCT images of the optic nerve head (24 radial scans) and peripapillary retina (1 circular scan). The angle between the fovea and BMO center (FoBMO), relative to the horizontal axis of the image frame, was first determined and all scans were acquired and analyzed relative to this eye-specific FoBMO axis. Variation of BMO-MRW and RNFLT was analyzed with respect to age, sector and BMO shape. Main Outcome Measures Age-related decline and between-subject variability in BMO-MRW and RNFLT. Results There were 246 eyes of 246 subjects with a median age of 52.9 (range, 19.8 to 87.3) years. The median FoBMO angle was −6.7° (range, 2.5° to −17.5°). BMO was predominantly vertically oval with a median area of 1.74 mm2 (range, 1.05 to 3.40 mm2). Neither FoBMO angle nor BMO area was associated with age or axial length. Both global mean BMO-MRW and RNFLT declined with age at a rate of −1.34 µm/y and −0.21 µm/y, equivalent to 4.0% and 2.1% loss per decade of life, respectively. Sectorally, the most rapid decrease occurred inferiorly and the least temporally, however, the age association was always stronger with BMO-MRW than with RNFLT. There was a modest relationship between mean global BMO-MRW and RNFLT (r = 0.35), while sectorally the relationship ranged from moderate (r = 0.45, inferotemporal) to non-existent (r = 0.01, temporal). Conclusions There was significant age-related loss of BMO-MRW in healthy subjects and notable differences between BMO-MRW and RNFLT in their relationship with age and between each other. Adjusting BMO-MRW and RNFLT for age and sector is important in ensuring optimal diagnostics for glaucoma.

Normal RNFL results with SOCT are comparable to those reported with time-domain OCT. In accordance with the literature on other devices, RNFL thickness measured with SOCT was significantly correlated with age and axial length. For creating a normative database of SOCT RNFL values have to be age adjusted.

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

We introduce a novel speckle noise reduction algorithm for OCT images. Contrary to present approaches, the algorithm does not rely on simple averaging of multiple image frames or denoising on the final averaged image. Instead it uses wavelet decompositions of the single frames for a local noise and structure estimation. Based on this analysis, the wavelet detail coefficients are weighted, averaged and reconstructed. At a signal-to-noise gain at about 100% we observe only a minor sharpness decrease, as measured by a full-width-half-maximum reduction of 10.5%. While a similar signal-to-noise gain would require averaging of 29 frames, we achieve this result using only 8 frames as input to the algorithm. A possible application of the proposed algorithm is preprocessing in retinal structure segmentation algorithms, to allow a better differentiation between real tissue information and unwanted speckle noise.