Researchers Discover a Gene Acts as a Master Regulator of Schizophrenia

Wednesday, September 18, 2019 - 16:27

Researchers from Children's Hospital of Philadelphia have discovered a gene that acts as a master regulator of schizophrenia during early human brain development.

According to the Science Daily report, the finding, which was released in Science Advances, may lay the groundwork for future treatments for the highly complex neuropsychiatric disorder.

"Because hundreds, or even thousands, of genes may contribute to the risk of schizophrenia, it is crucial to understand which are the most important ones, orchestrating core networks in the disease," said study leader Kai Wang, PhD, of the Department of Pathology and Laboratory Medicine and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT) at Children's Hospital of Philadelphia (CHOP).

The study appeared online in Science Advances. Wang co-led the research with Jubao Duan, PhD, the Charles R. Walgreen Research Chair and an associate professor at the Center for Psychiatric Genetics of North Shore University HealthSystem (NorthShore) and the University of Chicago, Evanston, Ill. The first author was Abolfazi Doostparast Torshizi, PhD, of the CCMT at CHOP.

The study team used computational systems biology approaches to discern a disease-relevant core pathway in schizophrenia and to discover a master regulator in that pathway that affects hundreds of downstream genes.

Observations showed that, when knocked down, the predicted TCF4 regulatory networks were enriched for genes showing transcriptomic changes, as well as for genes involved in neuronal activity, schizophrenia risk genes having genome-wide significance, and schizophrenia-associated de novo mutations.

Although some of the cellular effects of TCF4 dysregulation were previously shown in mice, Duan noted that the results from perturbing TCF4 gene networks in human stem cell models may be more relevant to the neurodevelopmental aspects of neuropsychiatric disorders.

The current study, said the researchers, sets the stage for further investigations. One direction, said Wang, is to use expanded datasets to explore whether other master regulators in addition to TCF4 may act in schizophrenia. If so, it may eventually be possible to classify patients with schizophrenia into subgroups more responsive to specific treatments, as is occurring in many cancers, to assist in implementing precision medicine in psychiatric diseases.

The study represents one of the first successful examples of combining computational approaches and stem cell-based experimental models to disentangle complex gene networks in psychiatric diseases.

Wang noted limitations in the study. The empirical validation focused on neural progenitor cells and glutamatergic neurons, but other cell types may be investigated in the future, such as interneurons and microglia, which have also been implicated in the development of schizophrenia.

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