Characterization of two modifier loci that alter the age-at-onset of glaucoma on chromosome 20
Authors: Vincent Raymond1, Pascal Belleau2, Rose Arseneault1, Jean-Louis Anctil3, Gilles Côté3, Marcel Amyot4, Stéphane Dubois1, Patrick Laplante1, Michael A. Walter5. 1CHUQ - Université Laval Research Centre, 2Cold Spring Harbor Laboratory, 3Ophtalmologie, Université Laval, 4Ophtalmologie, Université de Montréal, 5Medical Genetics, University of Alberta.
Author Disclosures: V. Raymond: None. P. Belleau: None. R. Arseneault: None. J. Anctil: None. G. Côté: None. M. Amyot: None. S. Dubois: None. P. Laplante: None. M.A. Walter: None.
Abstract Body:
Purpose: Primary open-angle glaucoma (POAG) is a complex genetic disease mainly caused by gene-gene interactions. Our goal is to characterize these gene-gene interactions as they could provide novel targets for treatment. In about 10 % of cases, POAG also segregates as an autosomal dominant (AD) trait that shows wide phenotypic variability. We hypothesize that this variability was caused by modifier genes that interact with the AD disease-causing genes. Characterization of these modifiers will lead to the identification of gene-gene interactions involved in the more complex non-mendelian forms of glaucoma.
Study Design: We studied the CA pedigree, a large French-Canadian AD glaucoma pedigree in which affected heterozygotes (HTZ) carry the myocilin ( MYOC ) K423E mutation. We developed systematic procedures to map modifier loci that contain genes which alter the ages-at-onset (AAO) of glaucoma. We then performed genotype-phenotype correlation studies to assess the effects of these loci on AAO and developed a novel unbiased family-based strategy to identify double-mutants who carry the MYOC K423E mutation and the modifiers.
Methods: Age-at-onset (AAO) was defined as the age at which intra-ocular pressure above 21 mm Hg was first detected. Modifier loci for variability of ages-at-onset (AAO) were mapped using genome wide linkage analysis and deep phenotyping. Because there was no efficient method to detect gene-gene interactions, we developed a novel unbiased family-based strategy to identify double-mutants who carry the modifiers and the MYOC mutation. This method was named DIGGI for Double-mutants that participate In Gene-Gene Interactions.
Results: The CA pedigree contains 709 members, of which 156 were heterozygotic carriers (HTZ) of the MYOCK423Emutation. Evaluation of ocular charts revealed that 120 HTZ had diagnoses ranging from juvenile open-angle glaucoma (JOAG) to adult-onset POAG while the remaining 36 HTZ were still asymptomatic even if many of them were older than 50 years of age. In the affected HTZ, AAO ranged from 7 to more than 60 years old. Using these HTZ, we then mapped at chromosome 20q13 and 20p12, two loci for variable age-at-onset of ocular hypertension (OHT), the 1st symptom of JOAG and POAG in the pedigree. We named these loci, Modifier Of Glaucoma locus 1 & locus 2 ( MOG1 & MOG2 ), respectively. Interestingly, the protective forms of the MOG1 & MOG2 haplotypes delayed the ages-at-onset of OHT by 8 to 10 years in branches of the pedigree. Combined with simulation and statistical studies, our data further show that the DIGGI procedure is highly reliable as it selects unequivocal double-mutants that participate in gene-gene interactions.
Conclusions: We mapped, at chromosome 20, two loci that encode DNA elements linked to extreme ages at onset for glaucoma. Protective forms of the MOG1 and MOG2 elements delayed the ages-at-onset of MYOC K423E glaucoma. These elements most probably hamper ocular hypertension. We further successfully applied to the case of glaucoma modifier genes, a powerful strategy to identify family members who shared common modifier haplotypes and alleles associated with specific endophenotypes for quantitative traits. The double-mutants that we identified are reliable individuals that will be used to find the nature and mechanisms of the MOG1 and MOG2 mutations.
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