AbstractsBiology & Animal Science

Current Genome-Wide Association Studies (GWAS) have successfully detected many genetic variants contributing to common diseases but not rare ones. Here two haplotype-based methods are proposed for detecting rare variants contributing a common disease. One method is a haplotype-based truncated product method (HTPM), for which we borrow a p-value combination method from testing for the multiple hypotheses, but use it for the purpose of clustering the information on rare risk haplotypes. The other method is the combined method, for which a set of risk haplotypes are chosen based on haplotype frequency comparison between cases and controls, and then tested using the same sample. Our simulation study demonstrates that both methods have increased power for detecting the association between rare variants and diseases, compared with other available methods. Both methods are applied to the Wellcome Trust Case Control Consortium (WTCCC) coronary artery disease and hypertension data and replicated the previous findings of genes associated with hypertension and coronary artery disease respectively at a genome-wide significance level of 5%. These results suggest that haplotype-based methods are powerful methods in searching for rare genetic variants and can be applicable to the data from current genome-wide association studies. Another part of this dissertation is a genetic association study of systolic and diastolic blood pressure (SBP and DBP) -the Candidate Gene Association Resource (CARe) Study. The CARe Consortium consists of a total of 8,591 AA and 20,082 for EA participants who were genotyped in seven United States cohorts. Participants who had SBP and DBP measures and genome-wide or candidate gene genotyping using the Affymetrix 6.0 array and Illumina IBC array, respectively were included in the association analysis. Primary association analyses were performed within each cohort using an additive genetic model; a meta-analysis combined data across all cohorts using inverse variance weighting. The strongest genome-wide signal identified in African Americans was rs10474346 (P=3.56x10-8), located near GPR98 and ARRDC3 on chromosome 5q14 for DBP; and rs2258119 in C21orf91 on chromosome 21 (P=4.69x10-8) for SBP. Suggestive evidence of association was detected for several genes.