Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J, Wei LJ, Sunyaev SR. Pooled association tests for rare variants in exon-resequencing studies. American Journal of Human Genetics (2010) 86: 832-838.
Multiple studies indicate strong association between rare variants and resulting phenotype. This paper describes a population-genetics simulation framework to study the influence of variant allele frequency on the corresponding phenotype. In a prior study, causal relationship between variants and phenotype was resolved by performing association test on set of variants having allele frequency below a fixed threshold. However, here it is observed that simulation frameworks based on a variable allele frequency threshold provide higher accuracy in association test compared to the fixed allele frequency model. In addition, inclusion of predicted functional effects of variants (Polyphen-2 scores) increases the accuracy of the variable frequency threshold model.
In conclusion, this paper describes a novel methodology, which can be used to explore the association between rare variants and various diseases.