Approaches for evaluating rare polymorphisms in genetic association studies

Most current genetic association studies, including genome-wide association studies, look for the single nucleotide polymorphisms (SNPs) with a relatively large minor allele frequency (MAF) (e.g. >5%) in the search for genetic loci underlying the susceptibility for complex diseases. The strategy of focusing on common SNPs in genetic association studies is very effective under the common-disease-common-variant (CDCV) hypothesis, which claims that common diseases are caused by common variants that have relatively small to moderate effects. Although the CDCV hypothesis has become the dogma guiding the conduct of association studies over the past decade, growing evidence from recent empirical data and simulations suggests that the causal genetic polymorphisms, including SNPs and copy number variants (CNVs), for common diseases have a wide spectrum of MAFs, ranging from rare to common. Unlike the analysis for common genetic variants, statistical approaches for the analysis of rare variants receive very little attention. Methods developed for common variants usually rely on their asymptotic properties, which can be inaccurate for the study of the rare variants with limited sample size. Although Fisher's exact test can be used for such a scenario, it is usually conservative and thus its usefulness is diminished to some extent. Here we propose two novel approaches for the analysis of rare genetic variants. Simulation studies and two real examples demonstrate the advantages of the proposed methods over the existing methods.