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

Abstract

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.

Keywords: endophenotype; family study; gene; glaucoma; heritability; twin study.