Researchers Map the Genetic Landscape of Schizophrenia in the Brain
Genes are known to play a key role in the risk for schizophrenia, but that genetic contribution is complex. A better understanding of the different genetic factors that contribute to the disorder and how they interact and combine to influence risk could improve treatments for schizophrenia. In an innovative study funded in part by the National Institute of Mental Health, researchers aimed to map the genetic landscape of schizophrenia in the brain. The study sheds light on biological risk factors that may play a role in schizophrenia and suggests potential therapeutic targets.
A multidisciplinary team led by Kynon Jade Benjamin, Ph.D., Apuã Paquola, Ph.D., Jennifer Erwin, Ph.D., and Daniel Weinberger, M.D., at the Lieber Institute for Brain Development and the Johns Hopkins University School of Medicine conducted a comprehensive analysis of gene activity in a specific region deep in the brain—the caudate nucleus. To date, there are no large-scale genetic analyses of the caudate nucleus, despite evidence that it is involved in schizophrenia and a key target of antipsychotic medications used to treat the disorder.
For this study, the research team analyzed postmortem tissue samples from 443 donors, which included adults who had either a schizophrenia or bipolar diagnosis and healthy controls with no known history of mental illnesses. The donors reflected a diverse mix of ancestries.
The researchers performed a comprehensive genetic and transcriptional analysis of the caudate nucleus. To do so, they identified candidate risk genes, gene features, and gene networks associated with schizophrenia and examined how changes in the DNA code translated into changes in the expression of RNA (the instructions copied from DNA and used to create cellular products such as proteins). Moreover, they examined whether a common environmental factor—the use of antipsychotics—influenced the changes in gene expression seen in the brains of people who had schizophrenia. This information was compared with other data, including gene expression in different brain regions and previous genetic risk factors.
This study represents a significant step forward in understanding risk factors for schizophrenia. The analyses showed altered expression in 2,700 genes in the caudate nucleus of people who had schizophrenia—several times more than the number of genes found in previous studies focusing on other brain regions. These included both genes identified in prior studies and new genes linked to schizophrenia for the first time.
To examine the effects of antipsychotics, caudate samples from people with schizophrenia were divided into those with and without exposure to the medication at the time of death. Antipsychotics had an extensive influence on caudate gene expression: 2,692 genes were differentially expressed between people on antipsychotics and controls, as compared to 665 differentially expressed genes between people without antipsychotics and controls. It should be noted that the genes with altered expression in people on antipsychotics overlapped largely with the genes associated with schizophrenia overall, making it difficult to disentangle the effects of antipsychotics from the effects of schizophrenia in general.
In-depth methods for analyzing gene expression data also revealed a role of the dopamine receptor gene, DRD2, in the genetic risk for schizophrenia. DRD2 is essential for regulating levels of dopamine (a chemical involved in communication between cells) in the brain. The researchers found decreased expression of a form of the receptor that regulates dopamine production and release in the caudate nucleus of people who had schizophrenia, which can lead to elevated dopamine levels. Although excessive dopamine is known to contribute to schizophrenia symptoms, this study is the first to identify a potential causal mechanism—reduced expression of a specific receptor—resulting in diminished control over dopamine activity. This novel finding of a link between a common genetic risk variant and activity of the dopaminergic system highlights a target for further investigation in treating schizophrenia.
Last, the researchers developed a new method for mapping gene networks that allowed them to plot connections between multiple genes with related biological functions that together may influence the risk for schizophrenia. They identified the largest gene expression changes in a network of genes involved in the development of neurons and signaling between neurons. Neurons are basic units of the brain that transmit information between the brain and other parts of the body. This finding suggests that schizophrenia or associated factors, such as medication use, may cause cellular-level changes in the structure and function of the brain. In turn, these biological changes may translate into downstream changes in cognition or behavior that emerge as symptoms of schizophrenia.
By employing a new method for mapping biological networks using gene expression data, the researchers identified “neighborhoods” of interconnected genes in the caudate nucleus. Understanding connections between genes in these networks is critical for developing treatments that target not only one but multiple genes that work together to increase risk. It can also shed light on the broader effects of treatments intended to target a single gene.
Benjamin, K. J. M., Chen, Q., Jaffe, A. E., Stolz, J. M., Collado-Torres, L., Huuki-Myers, L. A., Burke, E. E., Arora, R., Feltrin, A. S., Barbosa, A. R., Radulescu, E., Pergola, G., Shin, J. H., Ulrich, W. S., Deep-Soboslay, A., Tao, R., the BrainSeq Consortium, Hyde, T. M., Kleinman, J. E., … Paquola, A. C. M. Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes. Nature Neuroscience. https://doi.org/10.1038/s41593-022-01182-7