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Scientists recognize genes as master regulators in schizophrenia

Finding may offer a key target for future treatments.

Scientists recognize genes as master regulators in schizophrenia

Schizophrenia is a chronic and severe mental disorder that influences how a person thinks, feels, and carries on. People with schizophrenia may appear as though they have lost touch with reality.

It is a debilitating neuropsychiatric disease that affects about 1% of adults with heritability ranging from 73 to 83% in twin studies. However, its underlying genetic architecture remains incompletely understood.

Kai Wang, Ph.D., of the Department of Pathology and Laboratory Medicine said, “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.”

In a new study by the Children’s Hospital of Philadelphia (CHOP), scientists used computational tools to determine the gene transcription networks in extensive collections of brain tissues and investigated a gene that acts as a master regulator of schizophrenia during early human brain development.

Scientists 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.

Scientists analyzed two different datasets of biological samples from schizophrenia patients and control subjects. One dataset, the CommonMind Consortium (CMC), is a public-private partnership with well-curated brain collections. The other was a collection of primary cultured neuronal cells derived from olfactory epithelium (CNON), generated by study co-authors at the University of Southern California and SUNY Downstate.

The CMC dataset contained adult postmortem brain tissue, while the CNON dataset, used to validate findings from the CMC study, represented cell cultures that contain neuronal cells from nasal biopsies.

Applying an algorithm developed at Columbia University to reconstruct gene transcription networks, the study team identified the gene TCF4 as a master regulator for schizophrenia.

Wang said, “Previous genome-wide association studies (GWAS) had indicated that TCF4 was a locus for schizophrenia risk, but little was known of the ‘gene’s functional effects. We investigated those effects by knocking down, or decreasing, the ‘gene’s expression in neural progenitor cells and glutamatergic neurons derived from induced pluripotent stem cells in ‘Duan’s lab at NorthShore.”

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

Jubao Duan, Ph.D., the Charles R. Walgreen Research Chair and an associate professor at the Center for Psychiatric Genetics of North Shore University HealthSystem (NorthShore) said, “The results from perturbing TCF4 gene networks in human stem cell models may be more relevant to the neurodevelopmental aspects of neuropsychiatric disorders.”

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.

The study is published in the journal Science Advances..