Rare-variant collapsing analyses for complex traits: guidelines and applications

The first phase of genome-wide association studies (GWAS) assessed the role of common variation in human disease. Advances optimizing and economizing high-throughput sequencing have enabled a second phase of association studies that assess the contribution of rare variation to complex disease in all protein-coding genes. Unlike the early microarray-based studies, sequencing-based studies catalogue the full range of genetic variation, including the evolutionarily youngest forms. Although the experience with common variants helped establish relevant standards for genome-wide studies, the analysis of rare variation introduces several challenges that require novel analysis approaches. The increased adoption of DNA sequencing in genetic association studies is uncovering a wide range of population genetic variation, including rare genetic variants. Although this rarity limits the statistical power of associating individual rare variants with phenotypes, this Review discusses the diverse methods for leveraging the collective effects of rare variants in order to uncover important roles in complex traits, particularly human diseases.