During the last two decades, genotyping technology has advanced rapidly, which enabled the tremendous success of genome-wide association studies (GWAS) in the search of disease susceptibility loci (DSLs). However, only a small fraction of the overall predicted heritability can be explained by the DSLs discovered. One possible explanation for this ”missing heritability” phenomenon is that many causal variants are rare. The recent development of high-throughput next-generation sequencing (NGS) technology provides the instrument to look closely at these rare variants with precision and efficiency. However, new approaches for both the storage and analysis of sequencing data are in imminent needs. In this thesis, we introduce three methods that could be utilized in the management and analysis of sequencing data. In Chapter 1, we propose a novel and simple algorithm for compressing sequencing data that leverages on the scarcity of rare variant data, which enables the storage and analysis of sequencing data efficiently in current hardware environment. We also provide a C++ implementation that supports direct and parallel loading of the compressed format without requiring extra time for decompression. Chapter 2 and 3 focus on the association analysis of sequencing data in population-based design. In Chapter 2, we present a statistical methodology that allows the identification of genetic outliers to obtain a genetically homogeneous subpopulation, which reduces the false positives due to population substructure. Our approach is computationally efficient that can be applied to all the genetic loci in the data and does not require pruning of variants in linkage disequilibrium (LD). In Chapter 3, we propose a general analysis framework in which thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multi-loci analysis, which has focused on the dimension reduction of data, the proposed approach profits from the availability of large numbers of genetic loci. Thus it will be especially relevant for whole-genome sequencing studies which commonly record several thousand loci per gene.