Commingling Analysis of Intraocular Pressure and Glaucoma in an Older Australian Population

Abstract

SummaryPurpose: To test the hypothesis of a major genetic determinant of intraocular pressure (IOP) under the mixed genetic model in a defined population, and to elucidate the relationship between IOP and glaucoma. Methods: IOP was measured in 3654 persons attending the Blue Mountains Eye Study. A commingling analysis on IOP was performed using a new program, SKUDRIVER. The goodness of fit of 1-, 2-and 3-distribution models was measured. This was repeated after the glaucoma cases had been removed from the dataset, and further repeated on the glaucoma cases in the dataset. Results: The best model was 3-distribution with no evidence for Hardy-Weinberg disequilibrium. The proportion of variance explained by this major effect was 0.18. When glaucoma cases were removed, the best model had 2 distributions. There was no evidence of admixture in glaucoma patients. Conclusions:The findings of this study are consistent with the presence of a major gene accounting for 18% of the variance of IOP, which could therefore influence the risk of glaucoma, in this population. These findings suggest methods of optimizing strategies for family and association studies to identify quantitative trait loci for IOP. No evidence for distinct IOP-dependent and IOP-independent subgroups of glaucoma was found.

Heritability of intraocular pressure: a classical twin study

“…In previous work, the researchers estimated 36% heritability for IOP after adjusting for covariates 9. A commingling analysis from the Australian Blue Mountains Eye Study suggested the presence of a major gene contributing to 18% of the variance of IOP 10. Novel genetic loci for IOP have been identified,8 11 – 13 but not yet replicated.…”

Commingling Analyses of Central Corneal Thickness and Adjusted Intraocular Pressure in an Older Australian Population

“…This does not seem to be the case in the Blue Mountains Eye Study cohort. Previous commingling analyses on IOP 14 and optic disc morphology 13 do not suggest departure from HWE. Furthermore, a recent study 52 of the complement factor H (CFH) single-nucleotide polymorphism rs1061170 (Y402H) in this cohort identified CC, CT, and TT genotypes in 13.6%, 46.7%, and 39.7% of the population, respectively.…”

“…13,14 In brief, the analysis investigates whether the observed distribution of a quantitative trait is best modeled by a single distribution or by an admixture of multiple distributions. A single distribution suggests the lack of a single major genetic determinant for the trait, whereas multiple distributions suggest the presence of a major genetic determinant, especially if the distributions are in HardyWeinberg equilibrium (HWE) for population-ascertained data.…”

Biobanks and the importance of detailed phenotyping: a case study--the European Glaucoma Society GlaucoGENE project

“…However, genetic association studies on primary open-angle glaucoma have had conflicting results or have not been replicated 37. Poor specificity in the currently used phenotype parameters is a possible explanation,37 indicating that glaucoma genetics should focus on quantitative trait locus (QTL) studies, using variables such as intraocular pressure and cup-to-disc ratio 77 78…”