Exploring the Genetic Roots of Neurodevelopmental and Psychiatric Disorders

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Neurodevelopmental and psychiatric disorders (NPD) including schizophrenia, bipolar disorder, autism, and depression harms individuals, their families and society as a whole, and in many cases still lacks effective treatment. It is becoming more and more clear that genetic mutations in certain genes can increase the likelihood of developing NPD, and several hundred “risk genes” have been identified to date, but their role in relation to NPD remains unclear. a mystery “Very little is known about the basic function of most of these genes, and what we do know comes mostly from work in cancer cell lines rather than brain cell types,” ssaid David Panchision, Chief of the Developmental and Genomic Neuroscience Research Branch at the National Institute of Mental Health (NIMH), who led the SSPsyGene program aimed at addressing this challenge. “Because of this, we still don’t have a clear understanding of how changes in these genes might work individually or together to contribute to neurodevelopmental and psychiatric disorders.”

To understand this, the National Institute of Mental Health (NIMH) initiated a consortium called SSPsyGene (sspsygene.ucsc.edu) in 2023, bringing together research teams from prominent US universities with joint aimed to identify 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 and their teams, who developed a method for mutating NPD risk genes in human stem cells significantly. . 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 be turned into neurons and other brain cells to model the consequences of risk gene mutations in a simplified, lab-based version of the human brain. In the initial phase of the project, the teams tested 23 NPD risk genes, reported in work published in a recent journal article Stem Cell Reports. The resulting stem cell lines will be made available to other researchers around the world to facilitate research into risk genes and their contribution to NPD. In future work, Pang, Duan and other members of the consortium will work together to develop mutated stem cell lines for a larger number of risk genes, with the ultimate goal of understanding the genetic which is the cause for NPD and for the development of better treatments. “The hope is that this collaborative work will develop a highly influential resource for the neuroscience and psychiatric research community,” Panchision said.

Reference: Zhang H, McCarroll A, Peyton L, et al. Scaled and efficient derivation of loss-of-function alleles in risk genes for neurodevelopmental and psychiatric disorders in human iPSCs. Stem Cell Rep said. doi: 10.1016/j.stemcr.2024.08.003

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