Heterogeneous life events (LE) precede the onset of-and potentially increase the susceptibility to-panic disorder (PD). It remains unknown whether LE can act as moderators in the context of gene-by-environment interactions (G
7E) that alter the susceptibility to PD and the related trait of CO\u2082 sensitivity, nor it is known whether such moderation may depend on occurrence of events at different epochs in life. In 712 general population twins we analyzed by Maximum Likelihood analyses of ordinal data whether life (major- and stressful) events moderate the genetic risk for PD and CO\u2082 sensitivity, as indexed by the 35% CO\u2082 /65% O\u2082 challenge. For CO\u2082 sensitivity, best-fitting models encompassed both additive and interactional effects that increased linearly with the cumulative number and severity (SEV) of events in lifetime. By analyzing the moderation effect of cumulative SEV separately for events that had occurred in adulthood (between age 18 and 37) or during childhood-adolescence (before the 18th birthday), we found evidence of G
7E only within the childhood-adolescence window of risk, although twins had rated the childhood-adolescence events as significantly (P\u2009=\u20090.001) less severe than those having occurred during adulthood. For PD, all interactional terms could be dropped without significant worsening of the models' fit. Consistently with a diathesis-stress model, LE appear to act as moderators of the genetic variance for CO\u2082 sensitivity. Childhood-adolescence appears to constitute a sensitive period to the action of events that concur to alter the susceptibility to this panic-related trait
