The role of rare TIMP3 mutations in Age-Related Macular Degeneration. L. G. Fritsche, International AMD Genomics Consortium Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.

   Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. The disease typically has onset at 70 years of age. Disease progression results in loss of photo-receptors and ultimately leads to loss of central vision. Variants in 20 loci have been associated with susceptibility to AMD, including common non-coding variants near SYN3 and TIMP3, an especially attractive candidate gene. Mutations in TIMP3, particularly those that result in unpaired cysteine residues in the C terminus of the protein, can result in Sorsby fundus dystrophy (SFD; Weber et al., 1994). SFD is a rare autosomal-dominant retinal dystrophy that typically has onset 50 years of age. Disease progression is similar to that of age related macular degeneration, including choroidal neovascularization and pigment epithelium atrophy. To elucidate the potential role of rare TIMP3 mutations in late onset degenerative disease, we used genotyping arrays to examine 10 reported TIMP3 mutations and 44 other TIMP3 variants that, if present, would result in unpaired cysteine residues in 24,000 AMD cases and 20,000 controls. We observed 8 of these variants at least once in 40,633 unrelated Europeans. On aggregate, we identified 28 heterozygotes among 16,144 advanced AMD cases (with geographic atrophy or choroidal neovascularization) and one heterozygote in a single control. The burden of TIMP3 mutations was thus significantly enriched in advanced AMD patients (odds ratio = 30.1; P = 0.00081). Interestingly, the majority of this burden was accounted for by a predicted mutation TIMP3:p.(Ser38Cys) located in the N terminus of the protein. Mutations in the N terminus of TIMP3 have not been previously implicated in macular disease. The average age of onset for macular disease among mutation carriers was significantly younger (64.5 years vs. 76.8 years for non-carriers, P.000001), but still later than for typical cases of SFD. Phenotype re-evaluation of mutation carriers and segregation analysis in available family data is ongoing and will help clarify if TIMP3 mutation carrying AMD cases more closely resemble SFD cases than typical age-related disease. Our results illustrate how rare coding variants can contribute substantially to late onset disease and also illustrate an inexpensive approach for array based screening of 10,000s of individuals for interesting variants. The approach can be naturally extended to search for premature stop codons in many genes.

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