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Vincent Raymond, Pascal Belleau, Rose Arseneault, Stéphane Dubois, Jean-Louis Anctil, Gilles Côté, Marcel Amyot, Fahed Elian, Michael A Walter; Nature of the endophenotypes associated with the modifier for age-at-onset of glaucoma mapping at 20q13. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3425.
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We studied a large autosomal dominant open-angle glaucoma (OAG) pedigree in which heterozygotes (HTZ) for the myocilin MYOCK423E mutation displayed wide phenotypic variability. Diagnoses ranged from juvenile- (JOAG) to late-adult onset primary OAG (POAG) and several asymptomatic elderly HTZ were ≥ 55 years old. Our goals were to map modifier(s) interacting with MYOC and to define the altered endophenotypes.
375 members of the French-Canadian CA family were screened for mutations. Ocular records of all carriers were obtained. 4 quantitative traits were defined as endophenotypes: age of maximal intra-ocular pressures (IOPmax), IOP progression, progression of cup to disk ratios and, age-at-onset (AAO) defined as age at which IOP ≥22mmHg (ocular hypertension: OHT) or at which optic disk degeneration was first detected. Endophenotypes variabilities were tested for their heritability. Genotypes of 408 microsatellites in 184 CA members were analyzed using a Bayesian MCMC method in Loki. A pedigree-based three-stage algorithm was designed to optimize the probability of selecting unequivocal double-mutants, defined as MYOCK423E HTZ (affected and asymptomatic) who simultaneously carry potential mutations at the modifier locus.
156 individuals were found HTZ for MYOCK423E, 120 of these were OAG or OHT with treatment. AAO ranged from 7 to 63 years old. The other 36 HTZ were asymptomatic. Only AAO and IOPmax showed heritability, both with h2 ≥ 0.4. OHT was detected as the 1st symptom and preceded optic nerve damage in >98% of the affecteds, confirming that AAO was a reliable endophenotype to use for searching modifiers. Our genome-wide linkage analysis mapped a strong modifier locus for AAO at 20q13 with a maximal Bayes Factor = 27. It was named MOG1 (modifier of glaucoma). Saturation genotyping with SNPs refined MOG1 to a 9-10 cM interval between D20S857 and D20S430. When comparing the AAOs of the double mutants (MYOCK423E HTZ + MOG1 mutant) with the median AAOs of their respective neighbors (≤ 1st cousins) who were MYOCK423E HTZ but MOG1 wild-type, the modifier delayed the ages at onset of the double mutants by an average of 10 years.
The MOG1 locus encodes at least 1 DNA element linked to extreme ages at onset. It delays AAO of glaucoma by an average of 10 years. MOG1 interacts with MYOCK423E mutation most probably by hampering the first manifestations of OHT.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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