Led by scientists from the Children’s Hospital of Philadelphia, a new study has homed in on a single gene suggested to be a master regulator in schizophrenia. It’s hypothesized this master regulator gene directs the expression of a number of other genes during brain development, laying the groundwork for schizophrenia in later life.
Heritability for schizophrenia is high, possibly around 80 percent. Scientists are slowly identifying a number of genes associated with the condition, but it is increasingly looking like an incredibly large array of different genes all may play a part.
“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,” says Kai Wang, lead on the new research. “Pinpointing master regulators may help guide us toward priority targets for novel treatments in the future.”
A disease controlled by a single gene is often referred to as a monogenic disorder. When a number of genes are found to play a part in a condition, it is referred to as polygenic. In 2017 a team of Stanford scientists further broadened the genetic classification scale, coining the term omnigenic to describe traits or diseases where thousands of genes may play a role.
This new research suggests it is unclear whether schizophrenia is a polygenic or omnigenic disorder, but it is clear that a large number of genes are involved in the development of the condition. Wang says it is inevitable that some genes will be more important than others in the ultimate pathogenesis of the condition, so his team looked to uncover whether a master regulator gene could be identified.
Master regulators are genes that determine the expression of large numbers of other downstream genes. To home in on a possible master regulator gene for schizophrenia, the research team applied a novel algorithm to two separate datasets of biological samples. The algorithm was used to reconstruct gene transcription networks, and it ultimately focused on a gene known as TCF4.
TCF4 has previously been detected as a gene conferring schizophrenia risk, but this is the first time researchers have identified many of its functional effects. TCF4 was found to regulate a number of different gene networks involved in neuronal activity associated with schizophrenia, primarily in an early stage of neurodevelopment. Human stem cell models suggest the effect of TCF4 is most relevant in early development.
Wang notes that further research is underway to determine whether more master regulator genes play major roles in the development of schizophrenia. If other master regulators can be uncovered then Wang suggests schizophrenia patients could be classified into different subgroups, allowing for more targeted and precise treatments to be administered.
The new research was published in the journal Science Advances.
