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| Session Information |
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| Session Title: Statistical Genetics and Genetic Epidemiology Session Type: Poster |
| Session Location: Exhibit Hall C Session Time: Wed 4:30PM-6:30PM, Thu 4:30PM-6:30PM, Fri 10:30AM-12:30PM |
| Abstract Information |
| Poster Board Number: 2469/F Presentation Time: Fri, Nov 14, 2008, 10:30AM-12:30PM |
| Keywords: Statistical Genetics and Genetic Epidemiology, KW080 - GENOME-WIDE ASSOCIATION, KW086 - IDENTIFICATION OF DISEASE GENES, KW100 - MAPPING COMPLEX TRAITS, KW105 - MATHEMATICAL MODELING, KW163 - SUSCEPTIBILITY LOCUS |
| Abstract Content |
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Mathematical characterization of complex disease: Analytic expressions for the multi-locus additive model. F. Takeuchi, R. McGinnis Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. The degree of enrichment of disease-causing alleles in affecteds versus unaffecteds is perhaps the most important parameter determining detectability of loci responsible for complex diseases. In single-locus algebraic models of disease, the enrichment is markedly increased in related affecteds (RAs) from multiplex families compared to unrelated affecteds (UAs) from simplex families. However, the enrichment can be influenced by other disease-causing loci ("background loci") distinct from the locus being tested for association with disease (the "foreground locus"). Yet despite the important influence of background loci in modulating enrichment of disease alleles in RAs, this influence has not been studied extensively for one of the two main multi-locus algebraic models (i.e. the "additive"; model in which risks conferred by each locus are added to determine multi-locus penetrance). Furthermore, the few published investigations have relied mainly on simulations. We report here success in deriving analytic expressions that describe the multi-locus additive model including enrichment of disease allele frequency in RAs. One of our key findings is that the frequency of a disease-predisposing foreground genotype in RAs varies between the highly enriched frequency in the single-locus model and the unenriched frequency in unaffecteds. The degree of enrichment within this range is determined by the fraction of the disease recurrence risk among relateds (λR) which is contributed by the foreground locus as a proportion of total λR for the entire disease (i.e. foreground plus background loci). We have compared results from our derived equations with published simulation results for specific multi-locus additive models examined by Howson et al. (Genet Epidemiol 29:51, 2005) and Li et al. (Am J Hum Genet 78:778, 2006), and find close agreement with their results. We will illustrate how our analytic expressions can be used to address important issues such as appropriate study design and detectability of foreground disease loci by association testing given known magnitudes of familial aggregation (λR) in the particular disease being studied. |
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