Statistical methods for multi-marker testing in genetic association studies

As the development of genotyping and next-generation sequencing technologies, multi-marker testing in genome-wide association study and rare variant association study became active research areas in statistical genetics. This dissertation contains three methodologies for association study by exploring different genetic data features and demonstrates how to use those methods to test genetic association hypothesis. The methods can be categorized into in three scenarios: 1) multi-marker testing for strong Linkage Disequilibrium regions, 2) multi-marker testing for family-based association studies, 3) multi-marker testing for rare variant association study. I also discussed the advantage of using these methods and demonstrated its power by simulation studies and applications to real genetic data.

POPLAR GENE EXPRESSION DATA ANALYSIS PIPELINES

Analyzing large-scale gene expression data is a labor-intensive and time-consuming process. To make data analysis easier, we developed a set of pipelines for rapid processing and analysis poplar gene expression data for knowledge discovery. Of all pipelines developed, differentially expressed genes (DEGs) pipeline is the one designed to identify biologically important genes that are differentially expressed in one of multiple time points for conditions. Pathway analysis pipeline was designed to identify the differentially expression metabolic pathways. Protein domain enrichment pipeline can identify the enriched protein domains present in the DEGs. Finally, Gene Ontology (GO) enrichment analysis pipeline was developed to identify the enriched GO terms in the DEGs. Our pipeline tools can analyze both microarray gene data and high-throughput gene data. These two types of data are obtained by two different technologies. A microarray technology is to measure gene expression levels via microarray chips, a collection of microscopic DNA spots attached to a solid (glass) surface, whereas high throughput sequencing, also called as the next-generation sequencing, is a new technology to measure gene expression levels by directly sequencing mRNAs, and obtaining each mRNA’s copy numbers in cells or tissues. We also developed a web portal (http://sys.bio.mtu.edu/) to make all pipelines available to public to facilitate users to analyze their gene expression data. In addition to the analyses mentioned above, it can also perform GO hierarchy analysis, i.e. construct GO trees using a list of GO terms as an input.

STATISTICAL METHODS FOR RARE AND COMMON VARIANT ASSOCIATION STUDIES

Complex human diseases are a major challenge for biological research. The goal of my research is to develop effective methods for biostatistics in order to create more opportunities for the prevention and cure of human diseases. This dissertation proposes statistical technologies that have the ability of being adapted to sequencing data in family-based designs, and that account for joint effects as well as gene-gene and gene-environment interactions in the GWA studies. The framework includes statistical methods for rare and common variant association studies. Although next-generation DNA sequencing technologies have made rare variant association studies feasible, the development of powerful statistical methods for rare variant association studies is still underway. Chapter 2 demonstrates two adaptive weighting methods for rare variant association studies based on family data for quantitative traits. The results show that both proposed methods are robust to population stratification, robust to the direction and magnitude of the effects of causal variants, and more powerful than the methods using weights suggested by Madsen and Browning [2009]. In Chapter 3, I extended the previously proposed test for Testing the effect of an Optimally Weighted combination of variants (TOW) [Sha et al., 2012] for unrelated individuals to TOW &ndash F, TOW for Family &ndash based design. Simulation results show that TOW &ndash F can control for population stratification in wide range of population structures including spatially structured populations, is robust to the directions of effect of causal variants, and is relatively robust to percentage of neutral variants. In GWA studies, this dissertation consists of a two &ndash locus joint effect analysis and a two-stage approach accounting for gene &ndash gene and gene &ndash environment interaction. Chapter 4 proposes a novel two &ndash stage approach, which is promising to identify joint effects, especially for monotonic models. The proposed approach outperforms a single &ndash marker method and a regular two &ndash stage analysis based on the two &ndash locus genotypic test. In Chapter 5, I proposed a gene &ndash based two &ndash stage approach to identify gene &ndash gene and gene &ndash environment interactions in GWA studies which can include rare variants. The two &ndash stage approach is applied to the GAW 17 dataset to identify the interaction between KDR gene and smoking status.