Scientists want to decipher the genetic roots of mental illness on a large scale

Researchers have developed a method to mutate genes responsible for psychiatric and neurodevelopmental disorders (PNDs) in human stem cells on a large scale. In the modified cells, a selected psychiatric and neurodevelopmental disorder gene is mutated so that it no longer makes a functional protein. The modified stem cells can then be transformed into neurons and other brain cells to model the consequences of mutations in psychiatric and neurodevelopmental disorder genes in a simplified version of the human brain in the laboratory.

In the initial phase of the project, the teams tested 23 genes at risk for narcissistic personality disorder. They detail their work in an article in the journal Stem Cell ReportsThe resulting stem cell lines will be made available to other researchers around the world to facilitate research into these risk genes and their contribution to NPD.

Neurodevelopmental and psychiatric disorders (NDDs), including schizophrenia, bipolar disorder, autism, and depression, are detrimental to individuals, their families, and society as a whole, and in many cases there is still no effective treatment. It is becoming increasingly clear that genetic mutations in certain genes can increase the likelihood of developing NPD, and several hundred such “risk genes” have been identified to date, but their role in NPD remains a mystery.

“Very little is known about the basic function of most of these genes, and what we do know often comes from work in cancer cell lines rather than brain cell types,” says David Panchision, chief of the developmental neuroscience and genomics research branch at the National Institute of Mental Health (NIMH), who led the SSPsyGene program to address this challenge.

“We still do not clearly understand how alterations in these genes may act individually or in combination to contribute to neurodevelopmental and psychiatric disorders.”

To get to the bottom of this, the National Institute of Mental Health (NIMH) launched a consortium in 2023 called SSPsyGene, bringing together research teams from American universities with the common goal of characterizing the genetic origins of NPD, focusing on 250 selected high-risk genes.

Contributors include Jubao Duan, Endeavor Health (formerly NorthShore University Health System) and University of Chicago, USA, and Zhiping Pang, Rutgers University, USA, with their teams, who have developed a method for large-scale mutation of NPD risk genes in human stem cells. In the modified cells, a selected NPD risk gene is mutated so that it no longer produces a functional protein.

The modified stem cells can then be transformed into neurons and other brain cells to model the consequences of mutations in risk genes in a simplified version of the human brain in the laboratory.

In future work, Pang, Duan and other members of the consortium will join forces to generate stem cell lines mutated for a much larger number of risk genes, with the ultimate goal of understanding the genetic causes of NPD and generating better treatments.

“We hope that this collaborative work will generate a highly impactful resource for the neuroscience and psychiatric research community,” says Panchision.

Provided by the International Society for Stem Cell Research