Detecting rare variant associations: methods for testing haplotypes and multiallelic genotypes

We summarize the work done by the contributors to Group 13 at Genetic Analysis Workshop 17 (GAW17) and provide a synthesis of their data analyses. The Group 13 contributors used a variety of approaches to test associations of both rare variants and common single-nucleotide polymorphisms (SNPs) with the GAW17 simulated traits, implementing analytic methods that incorporate multiallelic genotypes and haplotypes. In addition to using a wide variety of statistical methods and approaches, the contributors exhibited a remarkable amount of flexibility and creativity in coding the variants and their genes and in evaluating their proposed approaches and methods. We describe and contrast their methods along three dimensions: (1) selection and coding of genetic entities for analysis, (2) method of analysis, and (3) evaluation of the results. The contributors consistently presented a strong rationale for using multiallelic analytic approaches. They indicated that power was likely to be increased by capturing the signals of multiple markers within genetic entities defined by sliding windows, haplotypes, genes, functional pathways, and the entire set of SNPs and rare variants taken in aggregate. Despite this variability, the methods were fairly consistent in their ability to identify two associated genes for each simulated trait. The first gene was selected for the largest number of causal alleles and the second for a high-frequency causal SNP. The presumed model of inheritance and choice of genetic entities are likely to have a strong effect on the outcomes of the analyses.