Relative power of linkage and transmission disequilibrium test strategies to detect non-HLA linked coeliac disease susceptibility genes

Abstract

Background: Susceptibility to coeliac disease is genetically determined by possession of specific HLA DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of familial risk is most parsimonious with a multiplicative model for the interaction between these two classes of genes. Haplotype sharing probabilities across the HLA region in affected sibling pairs suggest that genes within the MHC complex contribute no more than 40% of the sibling familial risk of coeliac disease, making the non-HLA linked gene (or genes) the stronger determinant of coeliac disease susceptibility. Attempts to localise these non-HLA linked genes have been carried out using both linkage and association tests.

Aims: To review the evidence for the involvement of non-HLA linked genes in coeliac disease, and to compare the relative merits of linkage and transmission disequilibrium tests (TDT) to detect the non-HLA linked gene (or genes) contributing to the development of coeliac disease.

Methods: Under a range of genetic models the number of affected sibling pairs needed to detect linkage was compared with the number of families required to show a relation between marker and disease, adopting the TDT strategy.

Results and conclusions: Power calculations show that, if there is a single major non-HLA linked susceptibility locus, a non-parametric linkage approach may well prove effective. However, if there are a number of non-HLA susceptibility genes, each with small effect, the sample size necessary for linkage studies will be prohibitive and a systematic search for allelic association should be a more effective strategy.

Figure 1

Effect of sibling relative risk and recombination on the probability of affected sibling pairs sharing two alleles identical by descent (IBD). Values based on the assumption that the sibling and parent-offspring relative risks are equal.