Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Correction: Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic etiology of ocular diseases.

Corneal hysteresis and corneal resistance factor are parameters that reflect the dynamic biomechanical properties of the cornea and have been shown to be biomarkers of corneal disease. In this genome-wide association study of over 100 000 participants, we identified over 200 genetic loci, all but eight novel, significantly associated with either one or both of these traits. In addition to providing key insights into the genetic architecture underlying normal corneal function, these results identify many candidate loci in the study of corneal diseases that lead to severe visual impairment. Additionally, using Mendelian randomization, we were able to identify causal relationships between corneal biomechanics and intraocular pressure measurements, which help elucidate the relationship between corneal properties and glaucoma.

Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development.

PURPOSE: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. DESIGN: A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. PARTICIPANTS: A total of 574 cases with PG or PDS and 52 627 controls of European descent. METHODS: Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. MAIN OUTCOME MEASURES: The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. RESULTS: Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). CONCLUSIONS: Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

Smoking, Corneal Biomechanics, and Glaucoma: Results From Two Large Population-Based Cohorts.

Purpose: Smoking may influence measured IOP through an effect on corneal biomechanics, but it is unclear whether this factor translates into an increased risk for glaucoma. This study aimed to examine the association of cigarette smoking with corneal biomechanical properties and glaucoma-related traits, and to probe potential causal effects using Mendelian randomization (MR). Methods: Cross-sectional analyses within the UK Biobank (UKB) and Canadian Longitudinal Study on Aging (CLSA) cohorts. Multivariable linear and logistic regression models were used to assess associations of smoking (status, intensity, and duration) with corneal hysteresis (CH), corneal resistance factor, IOP, inner retinal thicknesses, and glaucoma. Two-sample MR analyses were performed. Results: Overall, 68,738 UKB (mean age, 56.7 years; 54.7% women) and 22 845 CLSA (mean age, 62.7 years; 49.1% women) participants were included. Compared with nonsmokers, smokers had a higher CH (UKB, +0.48 mm Hg; CLSA, +0.57 mm Hg; P < 0.001) and corneal resistance factor (UKB, +0.47 mm Hg; CLSA, +0.60 mm Hg; P < 0.001) with evidence of a dose-response effect in both studies. Differential associations with Goldmann-correlated IOP (UKB, +0.25 mm Hg; CLSA, +0.36 mm Hg; P < 0.001) and corneal-compensated IOP (UKB, -0.28 mm Hg; CLSA, -0.32 mm Hg; P ≤ 0.001) were observed. Smoking was not associated with inner retinal thicknesses or glaucoma status in either study. MR provided evidence for a causal effect of smoking on corneal biomechanics, especially higher CH. Conclusions: Cigarette smoking seems to increase corneal biomechanical resistance to deformation, but there was little evidence to support a relationship with glaucoma. This outcome may result in an artefactual association with measured IOP and could account for discordant results with glaucoma in previous epidemiological studies.

Spectrum of Genetic Variants in the Most Common Genes Causing Inherited Retinal Disease in a Large Molecularly Characterized United Kingdom Cohort.

PURPOSE: Inherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large United Kingdom (UK) IRD patient cohort. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients with IRD who attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis was identified. METHODS: Genetic testing was undertaken via a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. Likely disease-causing variants were identified from entries within the genetics module of the hospital electronic patient record (OpenEyes Electronic Medical Record). Analysis was restricted to only genes listed in the Genomics England PanelApp R32 Retinal Disorders panel (version 3.24), which includes 412 genes associated with IRD. Manual curation ensured consistent variant annotation and included only plausible disease-associated variants. MAIN OUTCOME MEASURES: Detailed analysis was performed for variants in the 5 most frequent genes (ABCA4, USH2A, RPGR, PRPH2, and BEST1), as well as for the most common variants encountered in the IRD study cohort. RESULTS: We identified 4415 individuals from 3953 families with molecularly diagnosed IRD (variants in 166 genes). Of the families, 42.7% had variants in 1 of the 5 most common IRD genes. Complex disease alleles contributed to disease in 16.9% of affected families with ABCA4-associated retinopathy. USH2A exon 13 variants were identified in 43% of affected individuals with USH2A-associated IRD. Of the RPGR variants, 71% were clustered in the ORF15 region. PRPH2 and BEST1 variants were associated with a range of dominant and recessive IRD phenotypes. Of the 20 most prevalent variants identified, 5 were not in the most common genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1, and RP1. CONCLUSIONS: We describe the most common pathogenic IRD alleles in a large single-center multiethnic UK cohort and the burden of disease, in terms of families affected, attributable to these variants. Our findings will inform IRD diagnoses in future patients and help delineate the cohort of patients eligible for gene-directed therapies under development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

An Analysis of the Effect of ABCA4 p.Asn1868Ile Genotypes on Retinal Structure in 26,558 Participants in the UK Biobank.

Purpose: To determine whether the ABCA4 retinopathy-associated variant p.Asn1868Ile (c.5603A>T) is associated with retinal structure or subclinical disease among the general population. Methods: UK Biobank participants of European ancestry with available spectral-domain optical coherence tomography (OCT) passing quality control metrics and exome sequencing data were included. Regression analyses using both linear and recessive models tested for the association between the p.Asn1868Ile variant and total retinal thickness, clinically relevant segmented layer thicknesses, and visual acuity. Further regression analyses were performed with automated quality control metrics to determine if the p.Asn1868Ile variant is associated with poor quality or abnormal scans. Results: Retinal layer segmentation and sequencing data for the p.Asn1868Ile variant were available for 26,558 participants, following exclusions. We identified no significant association between the p.Asn1868Ile variant and retinal thickness, any of the segmented layers, or visual acuity. There was also no significant difference for homozygous p.Asn1868Ile when tested under the assumption of a recessive model. No association was identified for any of the quality control metrics, and a χ2 test showed that participants with the p.Asn1868Ile variant were not more likely to be excluded during quality control due to poor quality scans (P = 0.56). Conclusions: The p.Asn1868Ile variant does not appear to affect the retinal structure or have pathogenic or subclinical effects on its own within the general population. The variant is likely to require other specific cis- or trans-acting modifying factors to cause ABCA4 retinopathy.

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Genetic Heritability of Pigmentary Glaucoma and Associations With Other Eye Phenotypes.

Importance: Mechanisms behind pigmentary glaucoma, a form of early-onset glaucoma that may potentially lead to severe visual impairment or blindness, are poorly understood. Objective: To calculate the single-nucleotide polymorphism (SNP) heritability of pigmentary glaucoma and identify genetic associations with the disease. Design, Setting and Participants: This genome-wide association study included affected individuals from Germany and control participants from the United Kingdom. Genome-wide information was obtained for patients with pigmentary glaucoma and control participants free of glaucoma by using the Illumina Human Omni Express Exome 8v1-2 chip and genomic imputation. The SNP heritability of pigmentary glaucoma was estimated through a restricted maximum likelihood analysis. Associations between the genetic variants and pigmentary glaucoma obtained from age, sex, and principal component-adjusted logistic regression models were compared with those of SNPs previously associated with other eye phenotypes using Pearson product-moment correlations. Data were collected from November 2008 to January 2018, and analysis was completed between April 2018 and August 2019. Main Outcomes and Measures: An estimate of SNP-explained heritability for pigmentary glaucoma; correlations of effect sizes between pigmentary glaucoma and iris pigmentation and myopia; and correlations of effect sizes between pigmentary glaucoma and other eye phenotypes. Results: A total of 227 affected individuals (mean [SD] age, 58.7 [13.3] years) and 291 control participants (mean [SD] age, 80.2 [4.9] years) were included; all were of European ancestry. The SNP heritability of pigmentary glaucoma was 0.45 (SE, 0.22; P = 6.15 × 10-10). Twelve SNPs previously reported with genome-wide significant associations with eye pigmentation were associated with pigmentary glaucoma's SNP heritability (4.9% SNP heritability; 0.022; P = 6.0 × 10-4). Pigmentary glaucoma SNP effect sizes were correlated moderately for myopia (r, 0.42 [95% CI, 0.14-0.63]; P = 4.3 × 10-3) and more strongly with those for iris pigmentation (r = -0.69 [95% CI, -0.91 to -0.20]; P = .01), although this was nonsignificant per a strict adjusted significance threshold (P < .01). Conclusions and Relevance: These findings support the conclusion that pigmentary glaucoma may have a genetic basis and be highly heritable. Variants associated with lighter eye color and myopia appear to be associated with increased risk of pigmentary glaucoma, but no shared genetic basis with primary open-angle glaucoma (or its quantitative endophenotype of cup-disc ratio) was observed.

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects.

Purpose: The purpose of this study was to identify genetic variants on chromosome X associated with intraocular pressure (IOP) and determine if they possess any sex-specific effects. Methods: Association analyses were performed across chromosome X using 102,407 participants from the UK Biobank. Replication and validation analyses were conducted in an additional 6599 participants from the EPIC-Norfolk cohort, and an independent 331,682 participants from the UK Biobank. Results: We identified three loci associated with IOP at genomewide significance (P < 5 × 10-8), located within or near the following genes: MXRA5 (rs2107482, P = 7.1 × 10-11), GPM6B (rs66819623, P = 6.9 × 10-10), NDP, and EFHC2 (rs12558081, P = 4.9 × 10-11). Alleles associated with increased IOP were also associated with increased risk for primary open-angle glaucoma in an independent sample. Finally, our results indicate that chromosome X genetics most likely do not illicit sex-specific effects on IOP. Conclusions: In this study, we report the results of genomewide levels of association of three loci on chromosome X with IOP, and provide a framework to include chromosome X in large-scale genomewide association analyses for complex phenotypes.

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.