MOTIVATION: Genotype imputation, though generally accurate, often results in many genotypes being poorly imputed, particularly in studies where the individuals are not well represented by standard reference panels. When individuals in the study share regions of the genome identical by descent (IBD), it is possible to use this information in combination with a study-specific reference panel (SSRP) to improve the imputation results. Kinpute uses IBD information-due to recent, familial relatedness or distant, unknown ancestors-in conjunction with the output from linkage disequilibrium (LD) based imputation methods to compute more accurate genotype probabilities. Kinpute uses a novel method for IBD imputation, which works even in the absence of a pedigree, and results in substantially improved imputation quality. RESULTS: Given initial estimates of average IBD between subjects in the study sample, Kinpute uses a novel algorithm to select an optimal set of individuals to sequence and use as an SSRP. Kinpute is designed to use as input both this SSRP and the genotype probabilities output from other LD-based imputation software, and uses a new method to combine the LD imputed genotype probabilities with IBD configurations to substantially improve imputation. We tested Kinpute on a human population isolate where 98 individuals have been sequenced. In half of this sample, whose sequence data was masked, we used Impute2 to perform LD-based imputation and Kinpute was used to obtain higher accuracy genotype probabilities. Measures of imputation accuracy improved significantly, particularly for those genotypes that Impute2 imputed with low certainty. AVAILABILITY AND IMPLEMENTATION: Kinpute is an open-source and freely available C++ software package that can be downloaded from. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost.

Abstract Summary: Mixed model-based approaches to genome-wide association studies (GWAS) of binary traits in related individuals can account for non-genetic risk factors in an integrated manner. However, they are technically challenging. GLOGS (Genome-wide LOGistic mixed model/Score test) addresses such challenges with efficient statistical procedures and a parallel implementation. GLOGS has high power relative to alternative approaches as risk covariate effects increase, and can complete a GWAS in minutes. Availability: Source code and documentation are provided at http://www.bioinformatics.org/~stanhope/GLOGS. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

UNLABELLED: Computing the probability of identity by descent sharing among n genes given only the pedigree of those genes is a computationally challenging problem, if n or the pedigree size is large. Here, I present a novel graphical algorithm for efficiently computing all generalized kinship coefficients for n genes. The graphical description transforms the problem from doing many recursion on the pedigree to doing a single traversal of a structure referred to as the kinship graph. AVAILABILITY: The algorithm is implemented for n = 4 in the software package IdCoefs at http://home.uchicago.edu/abney/Software.html. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.