Recent advances and challenges of rare variant association analysis in the biobank sequencing era

Causal variants for rare genetic diseases are often rare in the general population. Rare variants may also contribute to common complex traits and can have much larger per-allele effect sizes than common variants, although power to detect these associations can be limited. Sequencing costs have steadily declined with technological advancements, making it feasible to adopt whole-exome and whole-genome profiling for large biobank-scale sample sizes. These large amounts of sequencing data provide both opportunities and challenges for rare-variant association analysis. Herein, we review the basic concepts of rare-variant analysis methods, the current state-of-the-art methods in utilizing variant annotations or external controls to improve the statistical power, and particular challenges facing rare variant analysis such as accounting for population structure, extremely unbalanced case-control design. We also review recent advances and challenges in rare variant analysis for familial sequencing data and for more complex phenotypes such as survival data. Finally, we discuss other potential directions for further methodology investigation.