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


OBJECTIVE
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.


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.
Bevan
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Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
Popat
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Houlston
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D000483:Alleles; D002446:Celiac Disease / Q000235:genetics*; D005805:Genes, MHC Class I; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D012306:Risk; D018401:Sample Size
D005819:Genetic Markers