A genome-wide analysis of 340 318 participants identifies four novel loci associated with the age of first spectacle wear.

Refractive errors, particularly myopia, are the most common eye conditions, often leading to serious visual impairment. The age of onset is correlated with the severity of refractive error in adulthood observed in epidemiological and genetic studies and can be used as a proxy in refractive error genetic studies. To further elucidate genetic factors that influence refractive error, we analysed self-reported age of refractive error correction data from the UK Biobank European and perform genome-wide time-to-event analyses on the age of first spectacle wear (AFSW). Genome-wide proportional hazards ratio analyses were conducted in 340 318 European subjects. We subsequently assessed the similarities and differences in the genetic architectures of refractive error correction from different causes. All-cause AFSW was genetically strongly correlated (rg = -0.68) with spherical equivalent (the measured strength of spectacle lens required to correct the refractive error) and was used as a proxy for refractive error. Time-to-event analyses found genome-wide significant associations at 44 independent genomic loci, many of which (GJD2, LAMA2, etc.) were previously associated with refractive error. We also identified six novel regions associated with AFSW, the most significant of which was on chromosome 17q (P = 3.06 × 10-09 for rs55882072), replicating in an independent dataset. We found that genes associated with AFSW were significantly enriched for expression in central nervous system tissues and were involved in neurogenesis. This work demonstrates the merits of time-to-event study design in the genetic investigation of refractive error and contributes additional knowledge on its genetic risk factors in the general population.

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.

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.

BACKGROUND/AIMS: To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency. METHODS: 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele. RESULTS: 211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants. CONCLUSIONS: There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

CYP2D6 basic genotyping as a potential tool to improve the antiemetic efficacy of ondansetron in prophylaxis of postoperative nausea and vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery. Ondansetron is one of the most widely used drugs in the prophylaxis of PONV and is extensively metabolized in humans. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes. The cytochrome P450 (human hepatic cytochrome [CYP]) 2D6 inhibitor quinidine reduced in vitro hydroxylation of ondansetron, which indicates the important role of CYP2D6 in ondansetron metabolism. Genotyping these alleles allows the prediction of the extensive metabolizer (EM) and poor metabolizer (PM) phenotypes with approx. 90-96% accuracy. OBJECTIVES: The aim of our study was to evaluate whether the pharmacological prevention of PONV with ondansetron depends on the most common CYP2D6 alleles (CYP2D6*1, *3, *4, *5, and NxN [multiplication gene]). MATERIAL AND METHODS: Genotyping for the defective CYP2D6*3, CYP2D6*4 and CYP2D6*5 alleles among 93 surgical female patients was performed by polymerase chain reaction amplification and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The genetically defined EMs and ultrarapid metabolizers (UMs) of CYP2D6 had a statistically significant (p < 0.02) higher frequency of nausea and vomiting after strumectomy (33.3%) than intermediate metabolizers (IMs) (10.3%) and PMs (0%). The relative risk (odds ratio [OR]) of PONV occurrence was 5 times higher for EMs/UMs than IMs/PMs. CONCLUSIONS: Our results suggest that PONV treatment with ondansetron could be improved by basic, widely available and inexpensive PCR-RFLP genetic tests.

Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

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.

INVOLVEMENT OF MULTIPLE MOLECULAR PATHWAYS IN THE GENETICS OF OCULAR REFRACTION AND MYOPIA.

PURPOSE: The prevalence of myopia has increased dramatically worldwide within the last three decades. Recent studies have shown that refractive development is influenced by environmental, behavioral, and inherited factors. This review aims to analyze recent progress in the genetics of refractive error and myopia. METHODS: A comprehensive literature search of PubMed and OMIM was conducted to identify relevant articles in the genetics of refractive error. RESULTS: Genome-wide association and sequencing studies have increased our understanding of the genetics involved in refractive error. These studies have identified interesting candidate genes. All genetic loci discovered to date indicate that refractive development is a heterogeneous process mediated by a number of overlapping biological processes. The exact mechanisms by which these biological networks regulate eye growth are poorly understood. Although several individual genes and/or molecular pathways have been investigated in animal models, a systematic network-based approach in modeling human refractive development is necessary to understand the complex interplay between genes and environment in refractive error. CONCLUSION: New biomedical technologies and better-designed studies will continue to refine our understanding of the genetics and molecular pathways of refractive error, and may lead to preventative and therapeutic measures to combat the myopia epidemic.

Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study.

Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.

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.

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium.

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

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.

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10-4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10-3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10-3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10-4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10-4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10-4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10-4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10-4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the "missing" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

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.

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.

Family history is a strong risk factor for prevalent angle closure in a South Indian population.

PURPOSE: To compare the prevalence of angle closure among siblings of patients with open angles (OAs), suspect angle closure (PACS), and either primary angle closure (PAC) or PAC glaucoma (PACG). DESIGN: Cross-sectional, clinical study. PARTICIPANTS: A total of 303 South Indian sibling pairs, including 81 OA probands, 143 PACS probands, and 79 PAC/PACG probands. METHODS: Probands and siblings underwent a clinical examination, including gonioscopy by a masked grader, applanation tonometry, slit-lamp biomicroscopy, optic nerve evaluation, and A-scan ultrasonography. Probands and siblings were classified into 1 of 3 groups based on the phenotype of the more severely affected eye: OA, PACS, or PAC/PACG. Multivariable regression models were used to estimate the odds of prevalent angle closure in PACS or PAC/PACG siblings compared with OA siblings. MAIN OUTCOME MEASURES: Prevalence and relative prevalence of angle closure and PAC/PACG among OA, PACS, and PAC/PACG siblings. RESULTS: Mean sibling age was 49.7 ± 8.7 years, and 56.6% of siblings were females. Angle closure was more prevalent in both PACS siblings (35.0%) and PAC/PACG siblings (36.7%) compared with OA siblings (3.7%; P < 0.001). There was PAC/PACG present in 11.4% of PAC/PACG siblings compared with 4.9% of PACS siblings (P = 0.07) and 0% of OA siblings (P = 0.002). In multivariable models adjusting for sibling age and sex, the odds of angle closure was 13.6 times greater in angle closure (PACS or PAC/PACG) siblings compared with OA siblings (95% confidence interval [CI], 4.1-45.0; P < 0.001). Sibling angle-closure risk was also greater in female (odds ratio [OR], 2.3; 95% CI, 1.3-4.0; P = 0.005) and older siblings (OR, 1.5 per 10-year increment; 95% CI, 1.1-2.0; P = 0.02). Siblings of PAC/PACG probands had a 2.3-fold greater odds (95% CI, 0.8-6.5) of having PAC/PACG compared with siblings of PACS probands, although the association was not significant (P = 0.13). CONCLUSIONS: In the South Indian population screened, siblings of angle-closure patients had a >1 in 3 risk of prevalent angle closure, whereas siblings of PAC/PACG patients had a >10% risk of prevalent PAC/PACG. Screening siblings of angle-closure patients is likely to be of high yield in finding undetected angle closure.

Genome-wide association studies of refractive error and myopia, lessons learned, and implications for the future.

The investigation of the genetic basis of refractive error and myopia entered a new stage with the introduction of genome-wide association studies (GWAS). Multiple GWAS on many ethnic groups have been published over the years, providing new insight into the genetic architecture and pathophysiology of refractive error. This is a review of the GWAS published to date, the main lessons learned, and future possible directions of genetic studies of myopia and refractive error.