Rare SNPs and structural variants have been implicated in complex disease (Bomba et al., 2017). Due to their more recent origin, rare variants tend to be more geographically clustered and can be population specific. They can also be particularly important from both clinical and biological perspectives because some confer a large increase in disease risk. However, there is severely limited power to identify trait associations of individual rare variants. Therefore, aggregation methods such as burden tests, variance-component tests, and hybrid tests have been developed to test the combined effect of several variants. Using this approach, variants can be combined within genes or regulatory genetic elements (Gilly et al., 2018; Kuchenbaecker and Appel, 2018). Ancestry groups may carry different driving variants at the same locus, as demonstrated by the association of different functional variants in ADH1B with alcohol use disorder in African Americans compared with European and Asian Americans (Edenberg and McClintick, 2018). Therefore, aggregate testing can be particularly suitable to projects involving different ancestral groups because they focus on functional units rather than individual variants and it is not necessary
