Determining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma

PURPOSE: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). // METHODS: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. // RESULTS: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. // CONCLUSIONS: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology

Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10(-61) ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however, the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank

Purpose: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. Design: Cross-sectional population-based study. Participants: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). Methods: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). Main Outcome Measures: Penetrance of glaucoma. Results: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5–306.6) adjusted odds of being in the top decile of PRS for POAG. Conclusions: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers

Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10-61 ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers