Associations between mosaic loss and schizophrenia or bipolar disorder of young onset

Mosaic chromosomal alterations (mCAs) accumulate in the brain tissues and are associated with psychiatric disorders. The association between mCAs in circulating blood and schizophrenia (SCZ) and bipolar disorders (BD) has not been fully evaluated. We detected mCAs from blood samples in 2,470 SCZ, 3,732 BD, and 177,773 control subjects. The associations between mCAs and SCZ or BD were evaluated using age-adjusted logistic regression models, further evaluated in age subgroups. The associations were further evaluated based on age at onset. We analyzed the associations between high cell fraction (CF) mosaic events (CF-mCAs >5% or CF-mCAs >10%) and SCZ or BD in the same way. Furthermore, we assessed the interaction between mCAs and genetic risk scores for SCZ or BD. Autosomal mCAs, especially mosaic loss events, increased in both SCZ and BD (SCZ; OR=1.78, P=4.9×10^-6, BD; OR=1.41, P=0.0025). These associations were highlighted in the young-age subgroup (SCZ; OR=7.01, P=1.7×10^-16, BD; OR=4.01, P=2.9×10^-8). We observed the strong effect sizes for association with the diseases at young onset (SCZ; OR=2.51, P=5.0×10^-5). In addition, the effect sizes of losses increased in a CF-dependent manner in both SCZ and BD. Loss events with high cell fraction interacted with polygenic risk score in SCZ (P=0.0098). SCZ or BD were characterized by the presence of a high burden of mosaic losses in blood, especially in onset of young age, suggesting the common somatic pathophysiological mechanisms between these psychiatric diseases. The possible interaction between losses and PRS for SCZ supports the genetic and environmental cross-talk in SCZ.