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Vincent Raymond, Pascal Belleau, Stéphane Dubois, Sylvie Desjardins, Eric Shink; An algorithm to characterize gene-gene interactions in family-based studies of polygenic disorders of the eye. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6395.
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One challenging task in polygenic disorders of the eye is to characterize genuine gene-gene interactions, while minimizing the risk of false negative findings. To detect such interactions, we developed an algorithm for pedigree-based studies of the eye. This algorithm optimizes the selection of reliable mutants to carry on successful genome-targeted sequencing within loci of interest. We exploited open-angle glaucoma as a model system.
Using a pedigree-based genome-wide linkage strategy, we recently mapped a modifier locus for variability of ages-at-onset (AAO) at chromosome 20p13 in a huge autosomal dominant open-angle glaucoma French-Canadian family. We next performed saturation genotyping of the locus with microsatellite and SNP markers in 184 members of the pedigree. Among them were 133 heterozygotes for the K423E myocilin mutation. This extensive dataset was then exploited to develop a three-stage algorithm.
In Stage 1, we define the specific genomic regions within the 20p13 locus (i.e. a marker allele or an haplotype) that are carried by individuals showing ages at onset which are either younger or older than that of other individuals within their neighborhood and who do not carry these regions (a neighborhood being all individuals with a relationship greater than that of, or equal to, a first degree cousin). The individuals carrying the identified regions are now called double-mutants since they harbor mutant regions within 20p13 and the K423E myocilin mutation. In Stage 2, we select from the double-mutants defined in 1, those who show higher contrasting ages at onset when compared to the AAO of the individuals, within their neighborhood, who only carry the K423E myocilin mutation. Finally in Stage 3, we position, within the pedigree, the double-mutants with higher contrasting AAO and ascertain their haplotype structures to refine the regions and to maximize potential imputations of the sequencing when it will be done in the pedigree.
To find genuine gene-gene interactions, we developed in a two loci system, a pedigree-based algorithm that optimizes the selection of reliable double-mutants for subsequent genome-targeted sequencing. This algorithm can be applied to all types of allelic markers and to many of the quantitative traits associated with polygenic disorders of the eye, for instance, age-related macular degeneration, myopia and glaucoma.
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