TLINKAGE-IMPRINT: a model-based approach to performing two-locus genetic imprinting analysis.

OBJECTIVES

Imprinting refers to the expression of only one copy of a gene pair, which is determined by the parental origin of the copy. Imprinted genes play a role in the development of several complex diseases, including cancers and mental disorders. In certain situations, two-trait-loci models are shown to be more powerful than one-trait-locus models. However, no current methods use pedigree structure efficiently and perform two-locus imprinting analyses. In this paper, we apply the Elston-Stewart algorithm to the parametric two-trait-loci imprinting model used by Strauch et al. [2000] to obtain a method for qualitative trait linkage analyses that explicitly models imprinting and can be applied to large pedigrees.

METHODS

We considered a parametric approach based on 4 x 4 penetrance matrix to account for imprinting and modified TLINKAGE software to implement this approach. We performed simulation studies using a small and a large pedigree under dominant and imprinted and dominant or imprinted scenarios. Furthermore, we developed a likelihood ratio-based test for imprinting that compares the logarithm of odds (LOD) score obtained using the two-locus imprinting model with that obtained using the standard two-locus model that does not allow for imprinting.

RESULTS

In simulation studies of three scenarios where the true mode of inheritance included imprinting, accurate modeling through the proposed approach yielded higher LOD scores and better recombination fraction estimates than the traditional two-locus model that does not allow for imprinting.

CONCLUSIONS

This imprinting model will be useful in identifying the genes responsible for several complex disorders that are potentially caused by a combination of imprinted and non-imprinted genes.