Mapping temporally varying quantitative trait loci in time to failure experiments

by Johannes, Frank.

Existing methods for mapping quantitative trait loci (QTL) in time-to-failure experiments assume that the QTL effect is constant over the course of the study. This assumption may be violated when the gene(s) underlying the QTL are up- or downregulated on a biologically meaningful time-scale. In such situations, models that assume a constant effect can fail to detect QTL in a whole genome scan. To investigate this possibility, we utilize an extension of the Cox model (EC-model) within an interval-mapping framework. In its simplest form, this model assumes that the QTL effect changes at some time point t0, and follows a linear function before and after this change point. The approximate time point at which this change occurs is estimated. Using simulated and real data, we explore the mapping performance of the EC-model to the Cox Proportional Hazards model (CPH-model), which explicitly assumes a constant effect. The results show that the EC- model detects timedependent QTL, which the CPH model fails to detect. At the same time, the ECmodel recovers all of the QTL the CPH-model detects. We conclude that potentially important QTL may be missed if their time-dependent effects are not accounted for. iii