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S.K. Iyengar, D. Song, B.E. K. Klein, R. Klein, J.H. Schick, J. Humphrey, C. Millard, G. Jun, K.E. Lee, R.C. Elston; Identification of a major locus and other oligogenic loci for age related macular degeneration in extended families . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2301.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We conducted a genome–wide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy to examine the genetic basis of age–related macular degeneration [AMD]. Methods: Index cases from the University of Wisconsin Retinal Clinic were asked to participate in a genetic study of AMD. Family and medical history was obtained from index cases and family members. All participating members had fundus photographs taken, which were graded for severity using the Wisconsin grading scheme. Model–free linkage analysis was performed and tests of heterogeneity and epistasis were conducted. Results: We have evidence of a major locus on chromosome 15q (GATA50C03 multipoint P = 1.98 x 10–7; empirical P ≤ 1.0 x 10–5). This locus was present as a weak linkage signal in our previous ARMD genome scan in the Beaver Dam Eye Study sample (D15S659 multipoint P=0.047), but is otherwise novel. In total we observed 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11 and 20q13) with a nominal multipoint significance level of P ≤ 0.01, or lod ≥ 1.18, in this genome scan. Family–by–family analysis of the data using model free linkage methods suggests that there is evidence of locus heterogeneity in these families. We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin–1 and EFEMP1 in a sub–sample (145 and 189 sib pairs respectively) of the data. Mutations were not observed in any of the 11 exons of EFEMP1, nor in exon 104 of hemicentin–1. The SNP analysis for hemicentin–1 suggests that variants within or in very close proximity to this gene on 1q31 cause ARMD pathogenesis. Conclusions: In summary, we have evidence for a major ARMD locus on 15q21, which, coupled with numerous other putative loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD
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