Heritability of glaucoma and glaucoma-related endophenotypes: Systematic review and meta-analysis

We have systematically extracted all available heritability (h2) estimates of glaucoma and related endophenotypes from the literature and summarized the evidence by meta-analysis. Glaucoma endophenotypes were classified into 10 clusters: intraocular pressure, anterior chamber size, central corneal thickness, cup-to-disc ratio, disc size, cup size, corneal hysteresis, retinal nerve fiber layer thickness, cup shape, and peripapillary atrophy. Random-effects meta-analyses were performed for each cluster. For clusters with n ≥ 10 h2 estimates, we also performed subgroup and meta-regression analyses. The literature search yielded 53 studies. The h2 of primary open-angle glaucoma ranged from 0.17 to 0.81, and was 0.65 for primary angle-closure glaucoma in a single study. The pooled endophenotype h2 estimates were intraocular pressure, 0.43 (0.38–0.48); anterior chamber size, 0.67 (0.60–0.74); central corneal thickness, 0.81 (0.73–0.87); cup-to-disc ratio, 0.56 (0.44–0.68); disc size, 0.61 (0.37–0.81); cup size, 0.58 (0.35–0.78); corneal hysteresis, 0.40 (0.29–0.51); retinal nerve fiber layer thickness, 0.73 (0.42–0.91); cup shape, 0.62 (0.22–0.90); and peripapillary atrophy, 0.73 (0.70–0.75). We identified mean age, ethnicity, and study design as major sources of heterogeneity. Our results confirm the strong influence of genetic factors on glaucoma and its endophenotypes. These pooled h2 estimates provide the most accurate assessment to date of the total genetic variation that can ultimately be explained by gene-finding studies.