Nature of the endophenotypes associated with the modifier for age-at-onset of glaucoma mapping at 20q13

Abstract

Purpose : We studied a large autosomal dominant open-angle glaucoma (OAG) pedigree in which heterozygotes (HTZ) for the myocilin MYOC^K423E 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.

Methods : 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 (IOP_max), 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 MYOC^K423E HTZ (affected and asymptomatic) who simultaneously carry potential mutations at the modifier locus.

Results : 156 individuals were found HTZ for MYOC^K423E, 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 IOP_max showed heritability, both with h² ≥ 0.4. OHT was detected as the 1^st 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 (MYOC^K423E HTZ + MOG1 mutant) with the median AAOs of their respective neighbors (≤ 1st cousins) who were MYOC^K423E HTZ but MOG1 wild-type, the modifier delayed the ages at onset of the double mutants by an average of 10 years.

Conclusions : 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 MYOC^K423E 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.