A Hypothesis for How Chromosome 11 Translocations Cause Psychiatric Disorders

Despite extensive effort for many years, the etiology of major psychiatric diseases remains unknown. A recent study by Baysal et al. has argued against the ALG9 gene variants in causing psychosis. Due to its disruption by a balanced t(9p24;11q23) translocation that segregates with the disorder in a family, it was proposed to be a primary candidate gene causing psychosis. In addition, a recent review article by Pickard et al., entitled “Cytogenetics and gene discovery in psychiatric disorders,” highlighted the importance of studies of chromosome rearrangements in finding disease-causing mutations. However, achieving the goal of finding genes by conventional association studies and by investigating chromosome rearrangements remains elusive. Here we discuss a fundamentally different explanation from the usual one considered by workers in the field concerning chromosome aberrations and psychoses etiology. We hypothesize how chromosome aberrations might cause disease but the gene at the rearrangement breakpoint is irrelevant for the etiology. Moreover, we discuss subsequently published findings that help scrutinize validity of the two very different hypotheses considered in the psychiatric genetics field. In sum, we alert the readers to the complexities of interpreting phenotypes associated with rearrangements.