Linkage and the Transmission Disequilibrium Test in Complex Traits: Celiac Disease as a Case Study

Many disorders such as celiac disease do not conform to a simple Mendelian model of inheritance and display a complex pattern of inheritance indicative of the interaction of a number of distinct susceptibility genes. Susceptibility to celiac disease is genetically determined by possession of specific HLA DQ alleles, acting in concert with one or more non-HLA-linked genes. Haplotypesharing probabilities across the HLA region in affected sibling pairs suggest that genes within the major histocompatibility complex (MHC) contribute no more than 30% of the sibling familial risk of celiac disease, making the non-HLA-linked gene (or genes) the stronger determinant of celiac disease susceptibility (1 ). Locating these non-HLA-linked genes can be undertaken by either linkage or association. The relative merits of these two approaches depend critically on the frequency and genotypic risks associated with susceptibility genes.