Abstract
About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with AMD, we used a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known AMD risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five SNPs in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.
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Acknowledgements
This research was supported by EY16335-02 (National Eye Institute K12 Harvard Vision Clinician Scientist Development Award); EY11309 from the US National Institutes of Health (National Eye Institute RO1 Grant, JMS) ; the Foundation Fighting Blindness; Massachusetts Lions Research Fund, Inc; the Macular Degeneration Research Fund, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center; and by the Broad Institute Center for Genotyping and Analysis, supported by Grant U54 RR020278 from the NCRR. LS is a recipient of a Research to Prevent Blindness Career Development Award and JMS was a recipient of the Research to Prevent Blindness Lew R Wasserman Award.
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Sobrin, L., Maller, J., Neale, B. et al. Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach. Eur J Hum Genet 18, 496–501 (2010). https://doi.org/10.1038/ejhg.2009.185
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DOI: https://doi.org/10.1038/ejhg.2009.185
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