Comparison of genotype clustering tools with rare variants

Background Along with the improvement of high throughput sequencing technologies, the genetics community is showing marked interest for the rare variants/common diseases hypothesis. While sequencing can still be prohibitive for large studies, commercially available genotyping arrays targeting rare variants prove to be a reasonable alternative. A technical challenge of array based methods is the task of deriving genotype classes (homozygous or heterozygous) by clustering intensity data points. The performance of clustering tools for common polymorphisms is well established, while their performance when conducted with a large proportion of rare variants (where data points are sparse for genotypes containing the rare allele) is less known. We have compared the performance of four clustering tools (GenCall, GenoSNP, optiCall and zCall) for the genotyping of over 10,000 samples using the Illumina’s HumanExome BeadChip, which includes 247,870 variants, 90% of which have a minor allele frequency below 5% in a population of European ancestry. Different reference parameters for GenCall and different initial parameters for GenoSNP were tested. Genotyping accuracy was assessed using data from the 1000 Genomes Project as a gold standard, and agreement between tools was measured.