Exact trait-model-free tests for linkage detection in pedigrees.

A number of trait-model-free tests have been proposed for linkage detection between a genomic region and a trait. These tests involve testing the dependence in segregation between a trait and marker alleles by assigning a score to every possible identity-by-descent configuration of the pedigree members without modeling the trait, and then averaging the scores over all such configurations compatible with the observed marker genotypes and genealogical relationship of the pedigree members. In this paper we propose a permutation test as an alternative to the existing exact trait-model-free tests for linkage detection. The proposed test is computationally efficient and is applicable on complex multigeneration pedigree structures. In this paper, we have compared the performance of the permutation test with two other exact trait-model-free tests for linkage detection on simulated datasets. We have demonstrated that the proposed permutation test is fully robust against mispecification of marker allele frequencies and has very good power for linkage detection. The permutation test is implemented in the program lm_ibdtests within the framework of MORGAN 2.8 (http://www.stat.washington.edu/thompson/Genepi/MORGAN/Morgan.shtml).