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Editors Selection IGR 8-3

Genetics

Comment by John Fingert on:

12522 Early adult-onset POAG linked to 15q11-13 using ordered subset analysis, Allingham RR; Wiggs JL; Hauser ER et al., Investigative Ophthalmology and Visual Science, 2005; 46: 2002-2005

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In their recent publication, Allingham et al. (443) present a new methodology to search for glaucoma genes by studying families with inherited disease. Most of the known glaucoma genes have been discovered by studying large pedigrees with positional cloning techniques such as linkage analysis. Although positional studies have been successful, a significant challenge to using this approach is the scarcity of large pedigrees necessary for research studies. This limitation has been addressed by analyzing pooled groups of small glaucoma families with the hypothesis that many families will have glaucoma due to a common genetic predisposition. In such a case, linkage data would be additive. However, the heterogeneity of glaucoma has limited the utility of studying groups of glaucoma pedigrees.

Allingham and coworkers used a method called ordered subset analysis (OSA) to perform linkage analysis on a subset of glaucoma pedigrees with the most similar phenotypes to minimize the problems of heterogeneity. Linkage analysis was performed on the pedigree with the earliest age at diagnosis (AAD). Additional pedigrees with the next most early AAD were then added one at a time and linkage analysis was repeated. Eighty-six pedigrees with primary open angle glaucoma were studied with OSA and linkage analysis. Attention was focused on a region of chromosome 15 that has been implicated as a glaucoma locus by prior studies. When 15 of the 86 pedigrees with the earliest AAD were analyzed a peak LOD score of 3.24 was detected and used to define a glaucoma locus (GLC1I) on chromosome 15q11-q13. No evidence for linkage was detected using the same approach with pedigrees ordered by other phenotypic characteristics of glaucoma (frequency of glaucoma-related blindness, degree of visual field loss, maximum recorded intraocular pressure, and frequency of surgical intervention). The use of OSA to phenotypically stratify pedigrees for iterative linkage calculations is a promising new approach for studying glaucoma genetics.

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