Genetic Heritability of Pigmentary Glaucoma and Associations With Other Eye Phenotypes

This genome-wide association study calculates the single-nucleotide polymorphism heritability of pigmentary glaucoma and identifies genetic associations with the disease. 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 x 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 x 10(-4)). Pigmentary glaucoma SNP effect sizes were correlated moderately for myopia (r, 0.42 [95% CI, 0.14-0.63]; P = 4.3 x 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. Question How heritable is pigmentary glaucoma, and are there shared genetic risks with other eye phenotypes? Findings This genome-wide association study of 227 affected individuals and 291 control participants estimated that 45% of disease variance is associated with common single-nucleotide polymorphisms. Pigmentary glaucoma appeared genetically distinct from primary open-angle glaucoma and its endophenotypes, but some single-nucleotide polymorphisms associated with eye color and myopia were correlated with those for pigmentary glaucoma. Meaning This study's findings support that pigmentary glaucoma may be heritable and found evidence for shared genetic architecture between myopia and iris pigmentation with pigmentary glaucoma.