Combination, Simulation, and Application of a Family-based Linkage and Association Study ---- dosage Transmission Disequilibrium Test (dTDT) for Linkage & Association Detection
Date of Award
Doctor of Philosophy (PhD)
Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this dissertation, we developed a novel approach to "infer" the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure of the interaction between a microsatellite marker and a SNP marker. Then we applied dTDT to the simulated data and documented the power of dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals.
As an outline, this dissertation in structured in the following way. In chapter 1, we start with a brief review of linkage and association studies, followed by a discussion on the challenges of dealing with missing data. The dTDT and its application to alcohol dependence are covered in Chapter 2 and 4 respectively. Chapter 3 demonstrates a follow-up simulation of the interaction between a microsatellite marker and a SNP marker as well as the application of dTDT on the simulated data.
Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.
Chair and Committee
Robert Culverhouse, Allison Goate, Charles Gu, Christina Gurnett, Andrew Heath, Nancy Saccone
Zhang, Zhehao, "Combination, Simulation, and Application of a Family-based Linkage and Association Study ---- dosage Transmission Disequilibrium Test (dTDT) for Linkage & Association Detection" (2012). Arts & Sciences Electronic Theses and Dissertations. 41.