Adaptation of the extended transmission/disequilibrium test to distinguishdisease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test

Linkage and association studies in complex diseases are used to identify an d fine map disease loci. The process of identifying the aetiological polymo rphism, the molecular variant responsible for the linkage and association o f the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically-linke d polymorphic markers flanking the disease variant, and the possibility tha t more than one polymorphism in the most associated region is aetiological, It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed f or detection of additional variants, such as the Haplotype Method, Marker A ssociation Segregation Chi-squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to te st for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the adva ntages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequili brium on the CETDT.