Genetic Architecture Of Open-angle Glaucoma: Modifiers Act Primarly By Causing Premature Elevation Of Intra-ocular Pressures

Abstract

Purpose: : Most often, chronic open-angle glaucoma (COAG, defined as in Shields Textbook of Glaucoma, 2011) is transmitted as a complex genetic disorder in which gene-gene interactions might be preponderant. To determine the mechanisms by which these interactions lead to COAG, we investigated the role of modifier genes on glaucoma severity in a huge autosomal dominant open-angle glaucoma family affected by a known disease-gene.

Methods: : Over the past 60 years, 700 members of the French-Canadian CA family were investigated. The records of 150 of them, who were heterozygotes for the myocilin (MYOC)^K423E mutation, were reviewed to analyze the heritability (h²) and clustering of seven (7) quantitative traits (QT) used as measurements for severity. The effects of WDR36 variations on these QTs were also studied.

Results: : The 7 QT values analyzed to quantify for severity were 1. intraocular pressures relative to age of the first IOP ≥ 22 mm Hg (age at onset, AAO), 2. maximal IOP (max), 3. number of years with at least 1 IOP value ≥ 22 mm Hg (nyIOP), 4. cup to disk ratio (C/D), 5. variation of cup to disk ratio relative to time periods (ΔC/D), 6. first C/D ≥ 0.7, and 7. the index I = log (K*(ΔC/D) / (L*(IOPmax)*(1+ nIOP/M) where K, L and M are constants. In our heterozygotes, only 2 traits, AAO and IOP max, were characterized as heritable traits relative to IOP with h² values at 0.57 and 0.4, respectively. The other QTs, evaluating optic nerve degeneration, showed no significant h² values. Similar data were obtained when the clustering of these QTs was tested. For instance, AAO clearly showed 7 clusters in the pedigree for younger or older AAO. To evaluate if the potential modifier gene WDR36 altered the expression of specific endophenotypes, we compared the QT values displayed by double mutants carrying 1 WDR36 variation plus the MYOC^K423E mutation to the medians of AAO displayed by simple mutants MYOC^K423E who shared a kinship coefficient ≥ 0.0625 (1st degree cousin or closer) with the double mutant. Interestingly, the majority of WDR36/ MYOC^K423E double mutants displayed a younger AAO when compared to their respective controls.

Conclusions: : Our study strongly suggests that MYOC-related modifier genes act primarily on mechanisms leading to premature elevated intraocular pressures. Our data also support WDR36 as a modifier gene that acts on mechanisms similar to those of other modifiers to elevate IOPs at young age.

Keywords: gene modifiers • genetics • trabecular meshwork