Goran Benčić

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case–control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

Heritabilities of Ocular Biometrical Traits in Two Croatian Isolates with Extended Pedigrees

PURPOSE To assess the effects of body stature and years of education, in addition to age and sex, on six oculometric traits and to estimate the heritabilities of these quantitative traits in two Croatian cross-population studies. METHODS Adult subjects living on the two Croatian islands of Vis and Korcula were recruited for a large epidemiologic and genetic study that included eye biometry, keratometry, and autorefraction. Effects and heritabilities were estimated by using general linear mixed models for axial length (AL), anterior chamber depth (ACD), corneal curvature (CC), corneal thickness (CT), lens thickness (LT), and spherical equivalent refraction (SER). Both cohorts were genotyped with dense SNP arrays, allowing the use of kinship coefficients derived from genotypic data (realized kinship) rather than from pedigree information (expected kinship). RESULTS Across cohorts, body mass index (BMI) did not consistently influence any of the ocular traits adjusted for age and/or sex, whereas height and years in education (YrEd) did, explaining up to an additional 5% of the variance (in CC). CT was the trait least influenced by covariates. Estimated heritabilities in Vis and Korcula, respectively, were 84% and 52% for CC, 75% and 71% for CT, 37% and 32% for LT, 59% and 45% for ACD, 37% and 74% for AL, and 0% and 17% for SER. CONCLUSIONS While heritabilities of CT and CC seemed uniformly high across studies of Caucasian datasets, estimates for SER varied widely and were at the lower end of the spectrum of published observations in our study.

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

Diabetic retinopathy image database(DRiDB): A new database for diabetic retinopathy screening programs research

Diabetic retinopathy is one of the leading disabling chronic diseases, and one of the leading causes of preventable blindness in the world. Early diagnosis of diabetic retinopathy enables timely treatment and in order to achieve it a major effort will have to be invested into screening programs and especially into automated screening programs. For automated screening programs to work robustly a representative fundus image database is required. In this paper we give an overview of currently available databases and present a new diabetic retinopathy database. Our database is to our knowledge the first and only database which has diabetic retinopathy pathologies and major fundus structures annotated for every image from the database which makes it perfect for design and evaluation of currently available and new image processing algorithms for early detection of diabetic retinopathy using color fundus images.

Comparison of A-scan and MRI for the measurement of axial length in silicone oil-filled eyes.

Aims: The aim of the study was to compare the accuracy of A-scan biometry and MRI for the measurement of axial length in silicone oil-filled eyes. Methods: This was a prospective randomised study of 70 patients. Biometry was performed using MRI in 33 patients (MRI group) and A-scan echography in 37 patients (A-scan group). The difference between predicted and final refraction was measured and evaluated statistically. Results: In patients with axial length ⩾26 mm, the mean deviation of the final from predicted refraction was −1.23 (SD 0.67) D in the MRI group and −2.3 (SD 2.02) D in the A-scan group. The difference between these two groups was statistically significant (p = 0.02). In patients with axial length <26 mm, the mean deviation of the final from predicted refraction was −0.12 (SD 1.29) D in the MRI group and −0.33 (SD 1.39) D in the A-scan group. There was no statistical significance between the two groups (p = 0.629). Conclusion: For highly myopic patients MRI biometry was a more accurate measurement of axial length in silicone oil-filled eyes. A-scan and MRI biometry were comparably accurate in measuring axial length in patients with axial length <26 mm.

Medical therapy for uveal effusion syndrome

PurposeTo report a case series of three patients with bilateral uveal effusion syndrome (UES), treated conservatively with oral carbonic anhydrase inhibitors and topical prostaglandin analogues (PAs).MethodsThree patients with bilateral UES were treated with the same initial therapy. Topical PA latanoprost 0.005% and acetazolamide 250 mg were administered in order to reduce intraocular pressure, improve uveoscleral outflow, and facilitate resolution of uveal effusion.ResultsThe chorioretinal detachment resolved within 3 months in two reported patients while the third one underwent surgery on his left eye. After clinical improvement, further oral therapy with acetazolamide was stopped, while topical prostaglandins were continued for at least the next 3 months. All patients were free from recurrence during the follow-up period.ConclusionAlthough the usually recommended UES therapy is partial or full-thickness sclerectomy, our case series showed apparent resolution of chorioretinal detachment in two patients on medical therapy alone. Conservative therapy may be the first step before the standard recommended surgical approach, but further studies are needed to verify the effectiveness of reported therapy.

High prevalence of glaucoma in Veli Brgud, Croatia, is caused by a dominantly inherited T377M mutation in the MYOC gene

An unusually high prevalence of early-onset open-angle glaucoma (OAG) in the population of Veli Brgud, Croatia, has been reported in previous studies.1 The most recent population census conducted in this isolated village in the mountains of Istrian peninsula (fig 1) reported a total of 550 inhabitants. Community-based ophthalmological examination was conducted during the 1990s among 536 inhabitants (97.5% of the total population) by the team of ophthalmologists from the University of Rijeka Medical School.1 OAG was diagnosed in 74 persons, and the population prevalence was found to be 13.8%. However, 67 (90%) of the affected individuals were linked to a single, large, nine-generation pedigree, while for the remaining seven persons with OAG, no link to the pedigree could be established. Although the village is isolated with high levels of inbreeding (proportion of consanguineous marriages is 22%), which usually favours the expression of recessive …

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

Retinal nerve fibre layer thickness measurements after successful retinal detachment repair with silicone oil endotamponade

Aims To measure peripapillary retinal nerve fibre layer thickness (RNFL) by using spectral domain optical coherence tomography (OCT) in patients who underwent successful retinal detachment repair with silicone oil tamponade. Methods Sixty patients treated with pars plana vitrectomy and silicone oil tamponade for retinal detachment were prospectively enrolled in a study. Peripapillary RNFL thickness was measured with a Cirrus HD-OCT at 7, 30, 90 and 180 days postoperatively, using an Optic Disc Cube 200×200 protocol. The fellow eye of each study patient served as a control. Median peripapillary RNFL thickness in silicone oil filled eyes was compared with control eyes. Results The median RNFL thickness in the group of vitrectomised eyes was significantly higher compared with control eyes at every visit. The analysis of variance showed that the median thickness in vitrectomised eyes differed between visits (F=4,3023; p=0.006). There was no time-related trend for RNFL thickness in this group. The analysis of variance of RNFL thickness in the fellow, unoperated eyes showed no difference between visits (F=2,3426; p=0.075). Conclusions In patients with silicone oil tamponade, peripapillary RNFL was significantly thicker in comparison with fellow unoperated eyes over a 6-month period. Trial registration number NCT 01255306.