THE POWER OF LINKAGE DETECTION BY THE TRANSMISSION DISEQUILIBRIUM TESTS/

Despite growing interest in the use of transmission/disequilibrium tes t (TDT)-type analysis in association studies, there has been surprisin gly scant attention paid to the issues as to what factors affect the p ower of the TDT for linkage detection. We demonstrate in this paper th at the power is a function of several genetic parameters including the recombination fraction, penetrance, the age of mutant disease allele, marker allele frequency, recurrent mutation rates at marker and/or di sease locus, and initial linkage disequilibrium. In general, TDT has g reater power to detect linkage for a 'recessive'-type model than for a 'dominant'-type model. Its power also is higher when there is greater differential in marker allele frequency between disease and normal ch romosomes. And since the presence of marker mutation and/or recurrent mutation at the disease locus, or the age of disease mutation, or the initial incomplete linkage disequilibrium, all hasten the process to r each linkage equilibrium, all of them can affect the power of TDT to d etect linkage. The effect of marker mutation rate or the mutation rate at the disease locus can be minimal if mutation rates are low. The re sults on the impact of recombination fraction and of age of mutation o n the power of TDT in linkage detection seem to be disheartening for g ene mappers of complex diseases: for a disease with small genetic infl uence, a vastly large sample size is needed to detect the linkage, if the marker is not very close to the disease locus. This is particularl y true if the disease is 'old'.