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G. Gong, O. Kosoko–Lasaki, G. Haynatzki, J.F. Lynch, H.T. Lynch, M.R. Wilson; Familial Aggregation in Genetic Studies of Primary Open–Angle Glaucoma . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3809.
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Purpose: To analyze the phenotypic and genotypic heterogeneity of primary open–angle glaucoma (POAG) as manifested in familial aggregations. 2. To examine the influence of familial aggregations on the outcomes of genetic studies. 3. To determine the effect of familial aggregation on the estimation of the frequency of mutations such as those in the myocilin (MYOC) gene in the general population. Methods: MEDLINE was searched to obtain articles concerning the effects of familial aggregation on the outcomes of genetic studies in general and in glaucoma research in particular. Results: Although POAG is a complex trait, a class of POAG with Mendelian inheritance exists in numerous families with different mutations at various loci, in consonance with the "common disease–rare alleles" theory. Five of the six loci identified to date have been linked to POAG through investigation of single pedigrees. The remaining locus has been mapped by selecting and pooling smaller extended families with high similarities in the mode of inheritance, degree of familial aggregation, tendency to be linked to the same loci, racial/ethnic background, and country of origin. Additional loci have been identified with a similar approach. Results from linkage analysis pooling sporadic and familial POAG with different racial/ethnic background are often not reproducible. The frequency of MYOC mutations that have actually caused POAG is more informative in assessing the contribution of MYOC mutations to the disease prevalence. Because of the high degree of familial aggregation, the percentage of POAG cases caused by MYOC in the general population is higher than its share among index cases. Conclusions: 1. Studies with single large pedigrees will remain as one of the leading approaches to the identification of POAG–causing germline mutations. 2. Pooling smaller pedigrees with high phenotypic and genotypic similarities is a promising approach but caution is needed. 3. Combining familial and sporadic cases in linkage analysis, as practiced commonly, deserves reconsideration since the two categories of POAG have apparent phenotypic, and possibly genotypic, differences. 4. Mutations causing POAG with high degree of familial aggregation tend to have higher prevalence in the general population than they appear among index cases with POAG.
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