Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development

Disrupted in Schizophrenia-1 (DISCI) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISCI polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISCI variants are loss of function in Wnt/GSK3 beta signaling and disrupt brain development. The DISCI variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISCI knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.