Age at onset anticipation in familial schizophrenia. Does the phenomenon even exist?

The discovery of dynamic mutations, like the expansion of unstable CG-rich trinucleotide repeat sequence mutations, has revived the interest in investigating the phenomenon of anticipation of age at onset of the illness (AAO) in familial schizophrenia. In those studies of parent-offspring pairs analyzed for AAO anticipation published to date, however, several ascertainment biases were not adequately controlled for. The present study focuses mainly on the age at investigation (AAI) bias, neglected so far, by investigating 96 schizophrenic parent offspring pairs and 26 aunt/uncle-niece/nephew pairs. When not controlling for a potential AAI bias, AAO differences in the parent-offspring sample in favor for anticipation were found in the same magnitude as reported by other authors (12.5 years, p < 0.0001). However, when controlling for AAI, these positive anticipation findings were compensated for (1.32 years, p=0.129). Additional selection procedures such as the exclusion of late-onset schizophrenia, the analysis of pairs where both members were through the age of risk, or the selection of aunt/uncle-niece/nephew pairs could not circumvent the AAI effect. These results suggest that the AAI effect is an essential bias in investigating anticipation, leading to false-positive AAO anticipation results if not taken into account.