Ophthalmology (Eye & Ear Hospital) - Research Publications
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ItemDiagnostic yield of candidate genes in an Australian corneal dystrophy cohort(WILEY, 2022-10)Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well-characterised cohort of 58 individuals from 44 families with different types of corneal dystrophy. Individuals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.
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ItemAttitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-10)PURPOSE: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an individual's risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected individuals toward PRS testing for glaucoma, and sought to identify factors associated with interest in testing. METHODS: We surveyed 418 unaffected individuals including 193 with a first-degree relative with glaucoma, 117 who had a recent eye examination, and 108 general members of the community. RESULTS: Overall, 71.3% of the individuals indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (odds ratio [OR] = 14.58, 95% confidence interval [CI] = 1.15-185.50, P = 0.039), those concerned about developing glaucoma (OR = 4.37, 95% CI = 2.32-8.25, P < 0.001), those with an intention to take appropriate measures regarding eye health (OR = 2.39, 95% CI = 1.16-4.95, P = 0.019), and those preferring to know if considered to be at-risk or not (OR = 4.52, 95% CI = 2.32-8.83, P < 0.001). CONCLUSIONS: Our results show strong interest in genetic risk assessment for glaucoma among unaffected individuals in Australia. TRANSLATIONAL RELEVANCE: These findings represent a valuable assessment of interest in glaucoma polygenic risk testing among potential target populations, which will be integral to the implementation and uptake of novel PRS-based tests into clinical practice.
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ItemRetinal ganglion cell-specific genetic regulation in primary open-angle glaucoma(ELSEVIER, 2022-06-08)To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
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ItemA saturated map of common genetic variants associated with human height(NATURE PORTFOLIO, 2022-10-27)Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
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ItemTranscriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration(NATURE PORTFOLIO, 2022-07-26)There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.
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ItemThe Relationship Between Fetal Growth and Retinal Nerve Fiber Layer Thickness in a Cohort of Young Adults(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-07)PURPOSE: To explore relationships between patterns of fetal anthropometric growth, as reflective of fetal wellbeing, and global retinal nerve fiber layer (RNFL) thickness measured in young adulthood. METHODS: Participants (n = 481) from within a Western Australian pregnancy cohort study underwent five serial ultrasound scans during gestation, with fetal biometry measured at each scan. Optic disc parameters were measured via spectral-domain optical coherence tomography imaging at a 20-year follow-up eye examination. Generalized estimating equations were used to evaluate differences in global RNFL thickness between groups of participants who had undergone similar growth trajectories based on fetal head circumference (FHC), abdominal circumference (FAC), femur length (FFL), and estimated fetal weight (EFW). RESULTS: Participants with consistently large FHCs throughout gestation had significantly thicker global RNFLs than those with any other pattern of FHC growth (P = 0.023), even after adjustment for potential confounders (P = 0.037). Based on model fit statistics, FHC growth trajectory was a better predictor of global RNFL thickness than birth weight or head circumference at birth. RNFL thickness did not vary significantly between groups of participants with different growth trajectories based on FAC, FFL, or EFW. CONCLUSIONS: FHC growth is associated with RNFL thickness in young adulthood and, moreover, is a better predictor than either birth weight or head circumference at birth. TRANSLATIONAL RELEVANCE: This research demonstrates an association between intrauterine growth and long-term optic nerve health, providing a basis for further exploring the extent of the influence of fetal wellbeing on clinical conditions linked to RNFL thinning.
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ItemSonic Hedgehog Intron Variant Associated With an Unusual Pediatric Cortical Cataract(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-06)PURPOSE: To identify the genetic basis of an unusual pediatric cortical cataract demonstrating autosomal dominant inheritance in a large European-Australian pedigree. METHODS: DNA from four affected individuals were exome sequenced utilizing a NimbleGen SeqCap EZ Exome V3 kit and HiSeq 2500. DNA from 12 affected and four unaffected individuals were genotyped using Human OmniExpress-24 BeadChips. Multipoint linkage and haplotyping were performed (Superlink-Online SNP). DNA from one affected individual and his unaffected father were whole-genome sequenced on a HiSeq X Ten system. Rare small insertions/deletions and single-nucleotide variants (SNVs) were identified in the disease-linked region (Golden Helix SVS). Combined Annotation Dependent Depletion (CADD) analysis predicted variant deleteriousness. Putative enhancer function and variant effects were determined using the Dual-Glo Luciferase Assay system. RESULTS: Linkage mapping identified a 6.23-centimorgan support interval at chromosome 7q36. A co-segregating haplotype refined the critical region to 6.03 Mbp containing 21 protein-coding genes. Whole-genome sequencing uncovered 114 noncoding variants from which CADD predicted one was highly deleterious, a novel substitution within intron-1 of the sonic hedgehog signaling molecule (SHH) gene. ENCODE data suggested this site was a putative enhancer, subsequently confirmed by luciferase reporter assays with variant-associated gene overexpression. CONCLUSIONS: In a large pedigree, we have identified a SHH intron variant that co-segregates with an unusual pediatric cortical cataract phenotype. SHH is important for lens formation, and mutations in its receptor (PTCH1) cause syndromic cataract. Our data implicate increased function of an enhancer important for SHH expression primarily within developing eye tissues.
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ItemNo Preview AvailableAttitudes Towards Polygenic Risk Testing in Individuals with Glaucoma(ELSEVIER, 2022-09)PURPOSE: Glaucoma is the leading cause of irreversible blindness worldwide; however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying individual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic; however, little is known about the attitudes of patients toward such testing. DESIGN: Cross-sectional, questionnaire-based study. PARTICIPANTS: Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. METHODS: One thousand one hundred sixty-nine individuals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. MAIN OUTCOME MEASURES: Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the individual would recommend the test to family members or others. RESULTS: Our results show strong interest in the test, with 69.4% of individuals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.15-2.49; P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05; 95% CI, 1.28-3.29; P = 0.003), and those who were worried about developing glaucoma (OR, 2.07; 95% CI, 1.27-3.37; P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. CONCLUSIONS: These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.
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ItemGenome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color(AMER ASSOC ADVANCEMENT SCIENCE, 2021-03)Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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ItemNovel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways(NATURE PUBLISHING GROUP, 2018-11-14)The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.