Characterization of unequivocal haplotypes that encode the 20q13 modifier for variable ages-at-onset of primary open-angle glaucoma

Abstract

Purpose : Primary open-angle glaucoma (POAG) is caused by gene-gene interactions. In 10 % of cases, POAG also segregates as an autosomal dominant (AD) trait that can show wide phenotypic variability. We hypothesize that this variability is caused by modifier genes that interact with AD disease genes. To detect significant gene-gene interactions, we designed a novel unbiased pedigree-based strategy that identifies double-mutants who harbor an AD disease mutation and simultaneously carry haplotypes encoding the modifier.

Methods : We studied a French-Canadian AD glaucoma pedigree in which 154 heterozygotes (HTZ) carry the MYOC^K423E mutation. Diagnoses ranged from juvenile OAG to late adult-onset POAG. Ages-at-onset (AAO), defined as age at which intra-ocular pressure ≥ 22mm Hg, ranged from 7 to > 60 y old. Several asymptomatic HTZ aged > 55 y old were also observed. Using the pedigree, we mapped a modifier locus for extreme variability of AAO at 20q13. It was named Modifier of Glaucoma 1, MOG1. To find reliable gene-gene interactions in humans, we developed a novel unbiased pedigree-based strategy. It was named DIGGI for Double-mutants that participate In Gene-Gene Interactions.

Results : DIGGI is a two-stage algorithm that exploits datasets obtained with diverse types of markers that can be coded, like microsatellites, VNTRs, SNPs and CNVs. The 1^st stage is the identification of MOG1 alleles, or marker haplotypes, associated with the modifier. The 2^nd stage is the identification of double-mutants who simultaneously carry the primary disease mutation and show higher contrasting ages at onset when compared to the AAO of individuals who are within their neighborhood (kinship coefficient defined as Φ(X,Y) ≥ 0.0625 where X and Y are people closer or equal to first degree cousins) and carry the myocilin K423E mutation. Robust double-mutants are positioned at the extremes of the extremes contrast distribution of the AAOs within their neighborhood. Simulation and statistical studies show that DIGGI is reliable at selecting unequivocal double-mutants that participate in gene-gene interactions.

Conclusions : We successfully applied to the case of glaucoma modifier gene a powerful strategy to identify family members who share common modifier haplotypes associated with specific endophenotypes for quantitative traits. These double-mutants will be used to characterize the MOG1 modifier.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.