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S.K. Iyengar, D. Song, B.E. Klein, R. Klein, J.H. Schick, K. Reading, R. Liptak, S.C. Tomany, K.E. Lee, R.C. Elston; Model Free Linkage Analysis in Extended Families Confirms a Susceptibility Locus for Age Related Macular Degeneration (ARMD) on 1q31 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2113.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify susceptibility genes for ARMD we conducted a genome-wide scan in a cohort of extended families ascertained through the retina clinic at the University of Wisconsin. Methods: Index cases in the Family Age-Related Maculopathy Study (FARMS) were persons with advanced ARMD who were asked whether they would be interested in participating in a study of the genetic correlates of ARM. All consenting subjects and family members were interviewed using a uniform interview schedule and had fundus photographs taken. The latter were graded using a codified grading scheme. Family members who lived at remote sites were sent to local clinics for blood draws and photographs. DNA was extracted from buffy coats and a genome scan performed using Weber Panel 10 markers (N=405).Three hundred and forty nine sib pairs in 34 extended families were genotyped and the data analyzed using the model free linkage analysis program SIBPAL (S.A.G.E. 4.2). Results: We observed that marker D1S518 on 1q31 demonstrated evidence for significant linkage (p = 0.004). A linkage signal was previously observed at this location in two genome scans conducted by other investigators (Klein M. et al, 1998 and Weeks et. al, 2001). Evaluation of the linkage evidence demonstrated that only a subset of families were linked to the markers at 1q31. Interestingly, we were unable to confirm evidence of linkage at this location in a previous genome scan in a population based cohort from Beaver Dam Wisconsin (N=325 sib pairs), even when allowing for both additive and dominant components. However, we were unable to exclude linkage in the Beaver Dam Eye Study (BDES) cohort, since the p-values for all these tests were less than 0.5 in this region. Conclusions: Since the ascertainment scheme for each genome scan, including the two previously reported scans and this study that gave a positive linkage signal on 1q31, was geared towards severe ARMD cases, we conclude that this locus harbors a susceptibility gene for ARM progression or severity. In contrast, the BDES consisted of sib pairs that were ascertained from a population-based epidemiologic cohort, where the individuals represented the continuum of severity, from mild to severe. We were unable to confirm evidence for linkage on 1q31 in the BDES sample as the effect of this susceptibility locus may be diminished due to locus heterogeneity, or because this sample consisted of a much smaller number of severely affected persons which led to reduced power.
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