<p>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.<P>
| Identifer | oai:union.ndltd.org:NCSU/oai:NCSU:etd-19990731-133658 |
| Date | 25 August 1999 |
| Creators | Nielsen, Dahlia |
| Contributors | Bruce Weir, Trudy Mackay, Ted Emigh, Sujit Ghosh |
| Publisher | NCSU |
| Source Sets | North Carolina State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://www.lib.ncsu.edu/theses/available/etd-19990731-133658 |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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