Association testing for rare variants is particularly sensitive to population stratification, and adjusting for fine-scale patterns of population stratification can be difficult with traditional methods (Zhang et al., 2013). In simulation studies, adjusting for PCs failed to fully control inflation for collapsing and variance-component methods (Persyn et al., 2018). Mixed effects models that have been developed for related samples might improve on this (Jiang and McPeek, 2014). However, this area requires further methods development.
