Other potential methods that leverage summary statistics to test multiple variant frequency differences across groups include classical DNA sequence diversity measures such as nucleotide polymorphism, θ, and nucleotide diversity, π47, as well as traditional measures of population differentiation such as that statistics referred to as Fst and Gst.48, 49 These methods are more or less agnostic to allele frequencies, but can provide insight into differences between groups over many rare variants. However, their utility and power have not been assessed in association analysis settings. In addition, flaws with measures such as Fst and Gst have been pointed out that may not allow them to reliably capture diversity, differences in diversity, or population differentiation in general in some of the most trivial settings, given their focus on heterozygosity.50 Jost50 discusses alternatives to traditional Fst, Gst and related DNA sequence population differentiation measures, but these measures still require assumptions about the best way to apply them in any one particular setting. Interestingly, the methods described by Jost can be easily adjusted to assess group differences attributable to many rare variants (see Box 3).50
