Browsing by Subject "Biology, Biostatistics"
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Item Open Access A Bayesian Hierarchical Model with SNP-level Functional Priors Applied to a Pathway-wide Association Study.(2010) Huang, WeiziTremendous effort has been put into study of the etiology of complex
diseases including the breast cancer, type 2 diabetes,
cardiovascular diseases, and prostate cancers. Despite large numbers of reported disease-associated loci,
few associated loci have been replicated, and some true associations
does not belong to the group of the most significant loci
reported to be associated. We built a Bayesian hierarchical model incorporated
with SNP-level functional data that can help identify associated SNPs in pathway-wide association studies.
We applied the model to an association study for the serous invasive ovarian cancer based on the DNA repair and apoptosis pathways. We found that using our model, blocks of SNPs located in regions enriched for missense SNPs or gene inversions were more likely to be identified as candidates of the association.
Item Open Access Characterization of Gene Interaction and Assessment of Ld Matrix Measures for the Analysis of Biological Pathway Association(2009) Crosslin, David RussellLeukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most notably asthma. Recently, leukotriene-based inflammation has also been implicated in atherosclerosis: ALOX5AP and LTA4H, two genes in the leukotriene biosynthesis pathway, have been associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a non-familial data set of early onset coronary artery disease. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility. Motivated by this need, we investigated the statistical properties of a class of matrix-based statistics to assess epistasis. We simulated multiple two-variant disease models with haplotypes to gain an understanding of pathway interactions in terms of correlation patterns. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequlibrium (LD) patterns with other haplotype markers. The simulated models can be summarized into three categories: 1. No epistasis in the presence of marginal effects and LD; 2. Epistasis in the presence of LD and no marginal effects; and 3. Epistasis in the presence marginal effects and LD. We then assessed previously introduced single-gene methods that compare whole matrices of Single Nucleotide Polymorphism (SNP) LD between two samples. These methods include comparing two sets of principal components, a sum-of-squared-differences comparing pairwise LD, and a contrast test that controls for background LD. We also considered a partial least-square (PLS) approach for modeling gene-gene interactions. Our results indicate that these measures can be used to assess epistasis as well as marginal effects under certain disease models. Understanding and quantifying whole-gene variation and association to disease using multiple SNPs remains a difficult task. Providing a single statistical measure per gene will facilitate combining multiple types of genomic data at a gene-level and will serve as an alternative approach to assess epistasis in genome-wide association studies. The matrix-based measures can also be used in pathway ascertainment tools that require scores on a gene-level.
Item Open Access Localized Correlation Analysis and Genetic Association with Cardiovascular Disease(2010) Ou, ChernHanVariations in gene expression are potential risk factors for atherosclerosis, which is one of the most common forms of cardiovascular disease. We performed a localized Pearson correlation test in 372 individuals from seven datasets relevant to cardiovascular disease studies. The genomes of samples were separated into 20Mb windows and correlation tests were performed locally in these windows. The localized Pearson correlation test found chr3:115Mb–135Mb was tightly connected by significantly high proportion of highly correlated pairs (P value = 0.0266 with Z-test). LSAMP, GATA2, MBD4, and other genes in the region were considered associated with cardiovascular disease because they were involved in highly correlated pairs. Furthermore, these genes were also associated with cardiovascular disease by having significantly high SNP odds ratios (P value < 0.1) between patients and controls in an independent Duke University Medical Center database. In addition, a permutation test was performed to demonstrate that chr3:115Mb–135Mb might underlie the regulation of cardiovascular disease. Finally, the localized Pearson correlation test also found some other regions that could be associated with cardiovascular disease.