Effect of polygenes on Xiong's transmission disequilibrium test of a QTL in nuclear families with multiple children

The transmission disequilibrium test (TDT), originally developed for mappin g disease genes, has recently been extended to identify quantitative trait loci (QTL). For quantitative traits important for human health, generally m ultiple QTLs are involved. In the investigation of the statistical properti es of the TDT, background polygenes (QTLs other than the QTL under test) ge nerally have not been explicitly considered. The effects of background poly genes on the statistical properties of the TDT are thus largely unknown. In vestigation of these effects will provide more realistic analyses of the st atistical properties of the TDT under biologically plausible situations, an d thus provide more accurate guidelines on the application of the TDT in pr actice. A general TDT (TDTG) has been developed to test linkage of a QTL in nuclear families that may be composed of more than one heterozygous parent and multiple children. Using the TDTG as an example, we develop an analyti cal method to investigate the effects of background polygenes on the power of the TDT. The accuracy of our analytical method is validated by computati on simulations. We found that the power of the TDTG is increased with backg round polygenes when more than one child is employed in nuclear families, a nd the effect is stronger with more children per family recruited for study . The power of the TDTG, increases dramatically when the number of children recruited from each nuclear family increases from one to two or from two t o three. The type one error rate is not affected by the presence of backgro und polygenes. The results of this study should be of theoretical significa nce in generalizing the investigation of the TDT to biologically plausible situations with background polygenes. They should also be of practical valu es in providing guidance on the recruitment of nuclear families with multip le children with the TDTG. Genet. Epidemiol. 21:243-265, 2001. (C) 2001 Wil ey-Liss, Inc.