An Examination of Association Based Tests for Localizing Genes in Outbred Populations
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1999-08-25
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Association based tests are designed to capitalize on evolutionaryforces and population history in order to localize genes affecting thetraits of interest to within very small regions. In the case-controltest, a sample of affected individuals (the cases) and a matched setof unaffected individuals (the controls) are collected, and markerallele frequency differences between the two groups are compared. Ifa significant difference between allele frequencies is found, it isdetermined that there is an association between the marker and adisease susceptibility locus. One shortcoming of this test is that ifthe cases and controls are not well matched, or if the controls arechosen from different subpopulations than the cases, spuriousassociations may be detected within the samples which do not reflectactual population values. Additionally, it is possible that genotypeinformation on a set of controls is simply not available. We explorethe relationship between Hardy-Weinberg disequilibrium among affectedindividuals at a marker locus and linkage disequilibrium between themarker and a disease susceptibility locus and show that there is aconnection between these disequilibrium measures which may be usefulfor detecting association using affected individuals only. As part ofthis work, we introduce two summary disequilibrium terms, one allelicand one genotypic, which appear as factors in variousassociation-based measures.Following up on several suggestive equations which led to the summarydisequilibrium terms, we examine the relationship between phenotypeand marker genotypes through the perspective of classical quantitativegenetics. Within this framework, we show that in a randomly matingpopulation there is a simple connection between the additive effectsof a marker locus and the additive effects of an associated traitlocus. An equivalent relationship holds between the dominancedeviations at the marker and the dominance deviations at the traitlocus. These relationships are captured by the summary disequilibriumterms introduced earlier.Using these results, we characterize the genetic properties that lociaffecting a quantitative trait must express in order for common testsof association to be able to detect them. We examine the case-controltest and the basic form of the transmission/disequilibrium test (TDT),and show that by focusing on alleles rather than on genotypes, thesetests are sensitive mainly to additive genetic effects at thesusceptibility loci. We offer several illustrations of theeffectiveness of these tests in detecting association under variousgenetic models.
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PhD
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Genetics
