Science has come a long way in understanding the genetic risk factors caused by psychiatric disease. Recent studies have discovered common genetic mutations that cause modest risk and rare variants, which cause a substantial risk, as for example the Disrupted in Schizophrenia-1 (DISC1) gene that was first identified in a large Scottish pedigree displaying schizophrenia as well as bipolar disorder and depression.

Typical DISC1 variants have been linked to altered cognition, brain structure and brain function, however how this occurs remained unknown. A new study that will be published in the November issue of Neuron shows how DISC1 variants impair signaling pathways and disrupt brain development.

The study is co-authored by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, and her team Karun K. Singh, Laurel Drane, Yingwei Mao, Zachary Flood and Cillian King.

Clues Provided By Signaling Pathways

Previous studies associated common DISC1 variants with abnormal brain development, however the functional impact remained unclear, as well as whether these mutations affect signaling pathways that influence brain structure. A framework provided by the new MIT study explains earlier reported links between DISC1 variants, psychiatric disorders and structural changes of the human brain. MIT researchers theorize that the effects on brain development linked to common DISC1 variants are the outcome of disruption in specific signalling pathways.

According to a recent report by the Picower Institute for Learning and Memory, DISC1 modulates Wnt signaling via GSK3β. Director Li-Huei Tsai of the Picower Institute explained:

“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.”

New approach enables more profound discovery

In the new study, supported by the National Institute of Mental Health and the Stanley Center for Psychiatric Research, the research team set out to obtain a better understanding of the functional impact of DISC1 genetic variation on brain development by experimenting with multiple model systems using mouse-, zebra fish- and human cells.

The findings provide proof that common and rare DISC1 variants have a negative effect on neurogenesis and neuronal migration via different signaling pathways. Researchers also discovered that three DISC1 variants interrupted Wnt/GSK3β signaling and neural progenitor cell proliferation. Although they noted that a fourth mutation did not impact Wnt signaling, it did suggest an inhibiting of neuronal migration in the developing cortex via another signaling pathway. They also noted that human cells that carried a particular variant demonstrated a greatly impaired Wnt signaling, whilst a different variant inhibited neuronal migration in the developing mouse cortex.

Findings potentially impact on diagnosis and treatment

Each one of the examined DISC1 variants was involved, both separately and during interaction, in regulating particular signaling pathways during brain development, influencing cortical structure and function and subsequently behavior. The researchers discovered that common variants, which affect baseline Wnt signaling could potentially become an early indicator of mental illness for some people, with the presence of additional risk genetic variants potentially providing further warning signs. Tsai commented:

“Our findings reveal an underlying association between DISC1 mutations, the distinct differences in human brains, and the onset of psychiatric disease.”

Because of the effect of certain DISC1 variants on Wnt signaling and brain development, this pathway could potentially play a significant part in mediating mood and psychiatric disorders.

Given that the common mood stabilizer lithium increases Wnt signaling, it may particularly benefit individuals suffering from bipolar disorder, as well as schizophrenic individuals with a specific genetic variant unresponsive to typical medication, which could benefit from increased efficacy of antipsychotic treatment. The findings enable researchers to gain a better insight into the mechanisms that regulate multiple processes during brain development, and how specific genetic variations could potentially contribute to mental illnesses.

Because future research will provide sequencing data for genes that regulate Wnt signaling and brain development, it will be crucial for scientists to understand how the interaction of these genes with the DISC1 variants influence the risk for psychiatric disorders.

Written by Petra Rattue