FounderRare: A Novel Statistical Package to Identify Rare Variants in Complex Diseases

FounderRare is a statistical package designed for the identification of rare variants in complex diseases. It leverages population genealogies, including those shaped by founder effects and identity-by-descent (IBD) segments, distinguishing it from other tools. This paper serves as a theoretical guide to the FounderRare package, illustrating its operations and capabilities. The package implements an IBD-based approach that computes the number of copies, among affected individuals, of the shared haplotype within genomic regions. The genome is partitioned into regions, within which clusters of affected individuals sharing specific IBD segments are identified. Statistical tests, denoted as S _msg and S _all , are included to evaluate the enrichment of IBD sharing among affected individuals. These tests rely on simulations of the null distribution and are designed to identify causal regions in the absence of control samples. FounderRare is optimized for cohorts comprising several thousand individuals—sample sizes typically required to achieve sufficient statistical power in rare variant analyses. By utilizing genotype array data, this tool enables cost-effective analysis at scale for researchers investigating complex diseases. It aids in pinpointing genomic regions likely to harbor rare variants, thereby contributing to a deeper understanding of the underlying genetic structure.

FounderRare, R package, rare variants, complex diseases, population genealogy, identical-by-descent (IBD) segments