In the era of big data in human genetics, large-scale biobanks aggregating genetic data from diverse populations have emerged as important for advancing our understanding of human health and disease. However, the computational and storage demands of whole genome sequencing (WGS) studies pose significant challenges, especially for researchers from underfunded institutions or developing countries, creating a disparity in research capabilities. We introduce new approaches that significantly enhance computational efficiency and reduce data storage requirements for WGS studies. By developing algorithms for compressed storage of genetic data, focusing particularly on optimizing the representation of rare variants, and designing regression methods tailored for the scale and complexity of WGS data, we significantly lower computational and storage costs. We integrate our approach into PLINK 2.0. The implementation demonstrates considerable reductions in storage space and computational time without compromising analytical accuracy, as evidenced by the application to the AllofUs project data. We improve runtime of an exome-wide association analysis of 19.4 million variants and a single phenotype from 695.35 minutes (approximately 11.5 hours) on a single machine to 1.57 minutes using 30Gb of memory and 50 threads (8.67 minutes using 4 threads). Similarly, we generalize to multi-phenotype analysis. We anticipate that our approach will enable researchers across the globe to unlock the potential of population biobanks, accelerating the pace of discoveries that can improve our understanding of human health and disease.