Seyhan Yazar

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10−8 for rs6445055), two on chromosome 9 (P = 2.80 × 10−11 for rs2472493 near ABCA1 and P = 6.39 × 10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10−11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Myopia is associated with lower Vitamin D status in young adults.

PURPOSE To investigate the association between serum vitamin D levels and myopia in young adults. METHODS A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D₃ (25(OH)D₃) concentrations were determined using mass spectrometry. The association between serum 25(OH)D₃ concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. RESULTS Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D₃ concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D₃ concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63; confidence interval [95% CI] 1.71-4.05; P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07; 95% CI 1.29-3.32; P = 0.002). CONCLUSIONS Myopic participants had significantly lower 25(OH)D₃ concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D₃ concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.

Myopia in Young Adults Is Inversely Related to an Objective Marker of Ocular Sun Exposure: The Western Australian Raine Cohort Study

PURPOSE To determine the association between ocular sun exposure measured by conjunctival ultraviolet (UV) autofluorescence and myopic refractive error in young adults. DESIGN Cross-sectional study. METHODS setting: Population-based cohort in Western Australia. study population: Total of 1344 mostly white subjects aged 19-22 years in the Western Australian Pregnancy Cohort (Raine) Eye Health Study. observation procedures: Cycloplegic autorefraction, conjunctival ultraviolet autofluorescence photography, participant questionnaire. main outcome measures: Prevalence of myopic refractive error (spherical equivalent less than -0.50 diopters) and area of conjunctival ultraviolet autofluorescence in mm(2). RESULTS There was an inverse relationship between myopic refractive error and ocular sun exposure, with more than double the prevalence of myopia in the lowest quartile of conjunctival autofluorescence than the highest quartile (33.0% vs 15.6%). Median area of autofluorescence was significantly lower in myopic than in nonmyopic subjects (31.9 mm(2) vs 47.9 mm(2), P < .001). These differences remained significant after adjustment for age, sex, parental history of myopia, and subject level of education. The use of corrective lenses did not explain the lower conjunctival autofluorescence observed in myopic subjects. CONCLUSIONS In this young adult population, myopic refractive error was inversely associated with objectively measured ocular sun exposure, even after adjustment for potential confounders. This further supports the inverse association between outdoor activity and myopia.

Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns

BackgroundSeveral individual studies have suggested that autosomal CpG methylation differs by sex both in terms of individual CpG sites and global autosomal CpG methylation. However, these findings have been inconsistent and plagued by spurious associations due to the cross reactivity of CpG probes on commercial microarrays. We collectively analysed 76 published studies (n = 6,795) for sex-associated differences in both autosomal and sex chromosome CpG sites.ResultsOverall autosomal methylation profiles varied substantially by study, and we encountered substantial batch effects. We accounted for these by conducting random effects meta-analysis for individual autosomal CpG methylation associations. After excluding non-specific probes, we found 184 autosomal CpG sites differentially methylated by sex after correction for multiple testing. In line with previous studies, average beta differences were small. Many of the most significantly associated CpG probes were new. Of note was differential CpG methylation in the promoters of genes thought to be involved in spermatogenesis and male fertility, such as SLC9A2, SPESP1, CRISP2, and NUPL1. Pathway analysis revealed overrepresentation of genes differentially methylated by sex in several broad Gene Ontology biological processes, including RNA splicing and DNA repair.ConclusionsThis study represents a comprehensive analysis of sex-specific methylation patterns. We demonstrate the existence of sex-specific methylation profiles and report a large number of novel DNA methylation differences in autosomal CpG sites between sexes.

Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Primary open‐angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta‐analysis of genome‐wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome‐wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup‐disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development

X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation revealed mild generalized cone system dysfunction and, in one patient, an interhemispheric asymmetry in visual evoked potentials. We show that CHRDL1 is expressed in the developing human cornea and anterior segment in addition to the retina. We explored the impact of loss of ventroptin function on brain function and morphology in vivo. CHRDL1 is differentially expressed in the human fetal brain, and there is high expression in cerebellum and neocortex. We show that MGC1 patients have a superior cognitive ability despite a striking focal loss of myelination of white matter. Our findings reveal an unexpected requirement for ventroptin during anterior segment development and the consequences of a lack of function in the retina and brain.

WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).

Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study

Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two‐step least squares instrumental‐variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta‐analysis of the three cohorts, using the PGRS as an IV, we estimated that each z‐score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10−3). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z‐score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.