Common genetic determinants of intraocular pressure and primary open-angle glaucoma.

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.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14.

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10⁻¹4). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42-2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

Heterogeneity of the genetic risk in age-related macular disease: a population-based familial risk study.

OBJECTIVE: To assess the extent of heterogeneity of the genetic risk of age-related macular disease (AMD) among families. DESIGN: Case-controlled population-based familial aggregation study. PARTICIPANTS: Participants comprised 190 first-degree relatives of 65 case probands and 347 relatives of 100 control probands. All probands had been identified from the baseline phase of the Rotterdam Study in The Netherlands. METHODS: A family score was computed for each family based on the presence and type of macular disease, the expected risk of disease, and the number, extent of kinship, and age of all family members. MAIN OUTCOME MEASURES: Presence and stage of AMD as diagnosed on fundus photographs, family score, and logistic regression coefficient. RESULTS: The family score of case families showed a peak of approximately 0 with a skewed tail (14% of families) of higher than expected risks of disease toward a maximum of 2.9. The family score of control families centered on 0, apart from 1 outlier. The risk of AMD increased significantly with higher family scores (beta = 1.34; P<0.001). CONCLUSIONS: The heterogeneity of genetic risk among AMD families is considerable, and the proportion of high-risk families is relatively small. The family score method is relevant for genetic counseling as well as for implementation in studies of genetic dissection of AMD.

Macular pigment and melanin in age-related maculopathy in a general population.

PURPOSE: It has been suggested that macular pigment (MP) and melanin may protect against age-related maculopathy (ARM). To check this, MP and melanin optical density were measured in a random population-based sample of subjects 55 years of age or older. METHODS: Spectral fundus reflectance of the fovea was measured in one eye per subject in a 2.3 degrees detection field with a fundus reflectometer. The sample consisted of 199 men and 236 women. Analysis with a fundus reflectance model yielded individual estimates for the MP and melanin optical density. Diagnosis of ARM was based on grading of standardized fundus transparencies. Eyes were stratified in four exclusive stages of ARM. RESULTS: MP optical density (at 460 nm) was 0.33 +/- 0.15 in eyes without ARM (n = 289) and 0.33 +/- 0.16 in eyes at any stage of ARM (n = 146). Melanin optical density (at 500 nm) was 1.18 +/- 0.19 in eyes without ARM and 1.20 +/- 0.21 in eyes at any stage of ARM. We found no gender differences for either MP or melanin optical density. CONCLUSIONS: No differences in MP and melanin optical density were found between eyes with and without ARM or between the various ARM stages.

Comparing ophthalmoscopy, slide viewing, and semiautomated systems in optic disc morphometry.

PURPOSE: To compare disc measurements obtained by indirect ophthalmoscopy, the Heidelberg Retina Tomograph (HRT), stereoscopic slide viewing (SSV) of color transparencies, and the Topcon ImageNet System (ImageNet). DESIGN: Population-based cross-sectional study. METHODS: From the Rotterdam Study, 324 subjects (567 eyes) were nonselectively included. All underwent a full ophthalmologic examination in mydriasis. Vertical cup/disc ratios (VCDRs) were compared between all four methods and disc area (mm(2)), neural rim area (mm(2)), cup area (mm(2)), and cup volume (mm(3)) between HRT and ImageNet. RESULTS: Mean VCDR for ophthalmoscopy was 0.25 (standard error [SE], 0.007), for HRT 0.42 (SE, 0.008), for SSV 0.39 (SE, 0.010), and for ImageNet 0.50 (SE, 0.006). The correlation for VCDR between ophthalmoscopy, the two devices, and SSV was 0.42, respectively 0.57; between ImageNet and HRT 0.75. The 97.5th percentiles of the VCDR for ophthalmoscopy, HRT, SSV, and ImageNet were 0.80, 0.73, 0.80, and 0.73, respectively; the 99.5th percentiles thus were 0.90, 0.79, 0.86, and 0.79. The mean disc area, rim area, cup area, and cup volume were 2.08, 1.63, 0.45 mm(2) and 0.09 mm(3) for HRT, and 2.39, 1.77, 0.61 mm(2) and 0.16 mm(3) for ImageNet, respectively. The corresponding correlations for these four parameters were 0.67, 0.42, 0.81, and 0.82. CONCLUSIONS: Different techniques lead to considerable differences in disc morphometric values. ImageNet produced higher mean values compared with HRT and ophthalmoscopy. Ophthalmoscopy showed the lowest correlations and SSV the highest ones with the two semiautomated devices. Between ImageNet and HRT the correlation for all parameters was high except for the neural rim area.