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Vincent Raymond, Pascal Belleau, Stéphane Dubois, Rose Arseneault, Éric Shink, Jean-Louis Anctil, Gilles Côté, Michael Walter, Marcel Amyot; Mapping of two modifier loci for glaucoma severity on chromosome 20. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6249.
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Primary open-angle glaucoma (POAG) is a polygenic disease caused by genetic and environmental risk factors. To understand how gene-gene interactions lead to POAG, it is essential to identify the modifiers that alter glaucoma endophenotypes. The goal of our study was to map such modifiers using families that showed variable expressivity of the disorder while segregating a primary disease-causing gene.
For the past 50 years, we have been investigating the French-Canadian autosomal dominant glaucoma CA pedigree (749 people) in which the MYOCK423E mutation expresses a very wide phenotypic variability. To assess heritability of the endophenotypes, all eye examination records of myocilin mutant carriers were revised to extract 6 quantitative trait values for glaucoma. Genome-wide linkage analysis were initiated by genotyping 408 microsatellite markers in 184 members. Linkage values were calculated using a Bayesian MCMC method implemented in LOKI. This procedure calculates L-score values by estimating the posterior probability of linkage divided by the prior probability. Interactions between modifier effects and MYOC were evaluated using MEON (Modifier Effects On Neighborhoods), a procedure developed to assess the strength of gene-gene interactions.
133 of the CA members were heterozygous for the MYOCK423E mutation with 114 of them affected. The other 17 heterozygotes were asymptomatic even if 9 of them were ≥ 35 years of age at their last exam. Only 2 of the traits selected for heritability analysis displayed a significant genetic component. Both were relative to intraocular pressures (IOP), 1. age-at-onset defined as age at which IOP raised ≥ 22 mm Hg and 2. maximal IOP. Our linkage analysis then revealed that two distinct 5 cM regions on chromosome 20 were linked to variable age-at-onset. The first locus, mapped at ~ 20q13, displayed an L-score value ≥ 10.The second locus, located between D20S189 and D20S898 at 20p12, showed an L-score value of ~ 8. Interestingly, these 2 markers mapped within the GLC1K locus that encodes a gene for early-onset OAG. Common modifier alleles identified the patients who contributed to the linked endophenotype.
We mapped two novel modifier loci for glaucoma severity. These 2 elements constitue a specific type of modifiers that might function by altering the age at which the first episode of intraocular hypertension occurs in mutant myocilin heterozygotes.
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