Significant progress has been made in understanding the genetic risk factors underlying psychiatric disease. Recent studies have identified common genetic mutations conferring modest risk and rare variants comprising significant risk. One example of a rare cause of psychiatric disorders is the Disrupted in Schizophrenia-1 (DISC1) gene, first identified in a large Scottish pedigree displaying schizophrenia, bipolar disorder and depression.

Common variants in DISC1 have been associated with altered cognition, brain structure and function, but it was unknown how this occurs. A new study co-authored by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, and her colleagues - Karun K. Singh, Laurel Drane, Yingwei Mao, Zachary Flood and Cillian King - demonstrates how DISC1 variants impair signaling pathways and disrupt brain development. This work is slated to appear in the November 17 issue of Neuron.

Signaling pathways offer clues
Earlier studies implicated common DISC1 variants in aberrant brain development, but the functional impact remained unclear, including whether these mutations affect the signaling pathways that influence brain structure. The new MIT study provides a framework to explain previously reported associations between DISC1 variants, human brain structural changes and psychiatric disorders. MIT researchers hypothesized that effects on brain development associated with common DISC1 variants are the result of disruption in specific signaling pathways.

The Picower Institute for Learning and Memory recently reported that DISC1 modulates Wnt signaling via GSK3β. Picower Institute Director Li-Huei Tsai commented: “The finding that DISC1 directly inhibits GSK3β is interesting given that the common mood stabilizer drug lithium and the schizophrenia risk gene Akt also inhibit GSK3β, which results in activation of canonical Wnt signaling, suggesting it may be an important target in psychiatric disease.”

Unique approach enables deeper discovery

In an effort to understand the functional impact of DISC1 genetic variation on brain development in the new study, the research team employed an experimental approach featuring multiple model systems spanning three species (mouse, zebrafish and human cells).

The study presents evidence that common and rare DISC1 variants negatively affect neurogenesis and neuronal migration via different signaling pathways. The neuroscientists’ findings demonstrate that three DISC1 variants disrupt Wnt/GSK3β signaling and neural progenitor cell proliferation. A fourth mutation does not impact Wnt signaling, but the research indicates that it inhibits neuronal migration in the developing cortex via another signaling pathway. Human cells carrying a particular variant displayed significantly impaired Wnt signaling, while a different variant inhibited neuronal migration in the developing mouse cortex.

Findings potentially influence diagnosis and treatment

All of the DISC1 genetic variants studied play a role, separately and during interaction, in regulating specific signaling pathways during brain development, thereby impacting cortical structure and function, and, ultimately, behavior. Common variants affecting baseline Wnt signaling may serve as an early indicator of mental illness for some individuals, while the presence of additional risk genetic variants might provide further warning signs. “Our findings reveal an underlying association between DISC1 mutations, the distinct differences in human brains, and the onset of psychiatric disease,” said Tsai.

Given that specific DISC1 variants affect Wnt signaling and brain development, this pathway may play a significant role in mediating mood and psychiatric disorders. Since the common mood stabilizer lithium increases Wnt signaling, as noted above, it may help bipolar sufferers in particular. Also, schizophrenia patients who carry a specific genetic variant and therefore don’t respond to typical medication may benefit from increased efficacy of antipsychotic treatment.

The results of this study provide greater insight into the mechanisms that regulate multiple processes during brain development and how specific genetic variations may contribute to mental illnesses. Given that future research will provide sequencing data for genes that regulate Wnt signaling and brain development, it will be critical to understand how DISC1 variant interactions with these genes influence risk for psychiatric disorders.
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This research was supported by the National Institute of Mental Health and the Stanley Center for Psychiatric Research.

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David M. Vaughn, Picower Institute
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617-452-3342
Massachusetts Institute of Technology