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S.L. Santangelo, C.–H. Yen, S. Chong, J.M. Seddon; A Discordant Sib–Pair Linkage Analysis of Age–Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2300.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We conducted a whole–genome linkage analysis using the extremely discordant sib–pair (EDSP) method to identify chromosomal locations for susceptibility genes for age–related macular degeneration (AMD). The use of EDSPs is a powerful alternative to conducting linkage analyses with concordant affected sib–pairs (ASPs), and requires fewer sib–pairs to reach the same power. Risch and Zhang (1995; 1996) showed that EDSP is superior to other sib–pair approaches whether or not there are multiple genes or rare alleles, and for all allele frequencies, degrees of dominance, heritabilities and genetic models, except rare recessives. For traits influenced by multiple genes with high allele frequencies, EDSP is the only sib–pair design with power to detect these genes. Methods: AMD classification was based on fundus photography and was assigned a grade ranging from 1 (no disease) to 5 (exudative disease) according to a modified grading system used in the Age–Related Eye Disease Study (AREDS Research group, 2001). Genotyping was performed by the NHLBI Mammalian Genotyping Service at Marshfield (Weber Screening Set 10: 404 short tandem repeat markers, average density 9 cM). Because the method is most powerful when sibs are maximally discordant, a sibship was designated an EDSP when at least one sib was affected with AMD (grades 3B, 4, 5), and had at least one sib who was totally asymptomatic (grade 1 and older than 60 years). Sibs with grades 2 and 3A were designated phenotype unknown. The sample included 42 families with 110 EDSPs. We searched for areas of the genome where the allele–sharing of the EDSPs was significantly decreased. Very few parents were available, which precluded assessment of alleles shared identical–by–descent. Therefore, the proportion of alleles shared identical–by–state was assessed using both a multiplicative and an additive model. Results: Modest evidence for linkage was found on chromosomes 1, 2, 6, 13, 19, and 20, with multipoint LOD scores ranging from 1.0 – 1.7. The regions identified on chromosomes 1, 2, and 6 were the same regions we identified in a prior analysis of 511 ASPs (Seddon et al., 2003). Given the modest sample size, these results are encouraging. Conclusions: In the absence of a true quantitative trait, the EDSP method of linkage analysis is a promising and powerful alternative to ASP linkage, which, to date, has been the only method used to search for linkage to AMD. Although the method is likely to be most efficient when EDSPs are combined with ASPs in a joint analysis, a sample of EDSPs alone will always be more powerful than the same size sample of ASPs.
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