The Ordered Transmission Disequilibrium Test: Detection of Modifier Genes

We consider the problem of detection of modifier genes that lead to variations in a disease-related Continuous variable (DRCV), Such as the age of onset or a measure of disease severity, in a strategy of candidate genes. We propose a novel method, the ordered transmission disequilibrium test (OTDT), to test for a relation between the clinical heterogeneity expressed by a DRCV and marker genotypes of a candidate gene. The OTDT applies to trio families with one patients and his parents, all three genotyped at a bi-allelic marker M. The OTDT aims to find a critical value of the DRCV which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions and compare it with a linear regression analysis. Genet. Epidemiol. 33:1-5, 2009. Published 2008 Wiley-Liss, Inc.