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Y. Wang, B. E. K. Klein, R. Klein, J. Capriotti, S. K. Iyengar; Susceptibility to Age-Related Macular Degeneration Is Mediated by Thrombospondin 1. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2105.
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Age-related macular degeneration (AMD) is the leading cause of blindness. In two previous genome scans for AMD we detected a major locus on chromosome 15q in samples from the Beaver Dam Eye Study (BDES) and the Family Age Related Maculopathy study (FARMS). Genes associated with AMD on chromosome 15 have not been reported in previous association studies, but thrombospondin 1 (THBS1), a matricellular protein, which is involved in retinal biology is an attractive candidate.
To test whether THBS1 is associated with AMD or related phenotypes, we performed a family-based association study in the FARMS samples (34 extended pedigrees, total 277 individuals). Sixteen single nucleotide polymorphisms (SNPs) with an average intermarker distance of 1Kb in THBS1 selected as tagging SNPs, were tested for association with five AMD measurements: a 15-step quantitative trait for AMD (AMD), power transformed 15-step scale (Pow.ARM), pigmentary abnormalities/ geographic atrophy (PA/GA), drusen size (Size), and drusen type (Type), using the ASSOC program in S.A.G.E. The AMD measures were obtained using 30 degree color stereoscopic graded fundus photographs of the eye. Models for additive, dominant and recessive modes of inheritance were tested for each SNP. To test whether they account for the linkage signal, these SNPs were added as a covariate in the linkage analysis using the SIBPAL program in S.A.G.E.
Analysis of the FARMS samples provided evidence for association between THBS1 with AMD. At a 0.05 significance level, SNPs rs11282 (P=0.0016), rs2664141 (P=0.03), rs2228263 (P=0.03), rs2228261 (P=0.0091), rs1051442 (P=0.05) were associated with Pow.ARM or Type. After correction for false discovery rate, rs11282 was still significant. SNPs rs2664141 (dominant), rs2228263 (dominant) and rs1051442 (additive) accounted for a modest decrease in the linkage signal.
These findings suggest THBS1 may play a role in AMD pathogenesis, however, this work needs confirmation from other studies. We continue to genotype this gene in other samples, e.g. BDES, to obtain confirmation of association.
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