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Karolinska Institutet and UNC School of Medicine researchers, including Patrick Sullivan, PhD, have identified four specific types of brain cells associated with schizophrenia. The findings offer a roadmap for the development of new therapies to target the condition.

The brain contains many different types of cells, all necessary for its function. But different cells are made of different building blocks (proteins) which all have different blueprints (genes). By combining a map of all building blocks used in the different cell types with lists of the blueprints known to be altered in people with schizophrenia, scientists could identify the types of cells that underlie the disorder. In a new study published today in Nature Genetics, researchers from the Karolinska Institutet in Sweden and the UNC School of Medicine show that indeed the genetics point towards certain cell types being much more implicated in schizophrenia than other cell types.

This research marks a transition in how scientists can use large genetic studies to understand the biology of disease.

“With the results from this study, we are giving the scientific community a chance to focus their efforts where it will give maximum effect” says Jens Hjerling-Leffler, PhD, one of the main authors.

Neuroscientists are proficient at identifying how problems with single genes or types of cells can cause disorders, but the great abundance of genes contributing to schizophrenia have made it difficult so far to design experiments.

“We have made great progress in understanding the genetic basis of schizophrenia and identifying the different cell types that exist in the brain,” said Patrick F. Sullivan, MD, FRANZCP, Yeargen Distinguished Professor of Psychiatry and Genetics and Director of the Center for Psychiatric Genomics at the University of North Carolina School of Medicine. “We connected these two different areas by asking which brain cell types best ‘fit’ the genetic results. Our results were clear: it wasn’t every cell type but rather four specific types of cells. This is important because they probably form a circuit. Schizophrenia is one of the hardest problems in medicine. We do not yet have the full understanding we need, but our paper will really help with focusing on only the right cell types for us to study and to model.”

Schizophrenia is an often devastating disorder causing huge human suffering; there have been many hypotheses as to where the cause of schizophrenia lies in the brain but no consensus has been reached between scientists. A key problem in the study of the biology of schizophrenia has been that the brain is like a black box: it is the most complicated structure in the known universe.

Genetic studies have linked hundreds of genes to schizophrenia, each contributing a small part to the risk of the disorder. This has left scientists struggling to understand what the common thread is linking all these genes together. One basic question is whether these genes affect the entire brain diffusely or certain components more.

The study found that common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs), and certain interneurons, but far less consistently to embryonic, progenitor or glial cells.

To reach this point one first needs a map of all the building blocks necessary for each cell type – this was achieved at Karolinska over the last couple of years. One then needs to combine this with a detailed blueprint of building blocks affected in disease: this has become available as a result of a major international collaboration known as the Psychiatric Genomics Consortium, which is based at the UNC School of Medicine and includes more 800 investigators from 38 countries around the world.

One striking finding was that there appears to be a few major cell types contributing to the disorder, each of which originates in a distinct area of the brain. This raises the question of whether each cell type underlies a distinct form of the disorder; this could explain why distinct symptoms are seen across patients with the condition. Alternatively, it could be the case that each cell type needs to be affected to trigger symptoms; this would have important implications for development of new treatments, as separate drugs may be required for each cell type involved.

Scientists say the findings offer a roadmap for the development of new therapies to target the conditions.

Nathan Skene, PhD, one of the lead authors on the study from the Karolinski Institutet, said, “Understanding which cell types are affected in disease is of critical importance for developing new medicines to improve their treatment. If we do not know what causes a disorder we cannot study how to treat it”

It is only now that it has become possible to study diseases in this way though as a result of exponentially rapid progress in two separate fields of science: human genetics and single cell transcriptomics. The researchers say that in coming years the approach should lead to breakthroughs in the biological understanding of other complex disorders such as autism and depression.

”The past decade has witnessed huge advances in our understanding of the genomic underpinnings of brain disorders. However, genomics is static by nature and do not provide inside into the dynamics of brain biology and much less brain pathology. The current study provides this insight at the single cell level allowing the translation of genomics risk variants into the identification of cell types, developmental processes and timing of brain pathologies, and eventually of biological targets for drug discovery,” said Thomas Werge, clinical professor at the Institute of Biological Psychiatry at the Copenhagen University Hospital, who was not involved in the current study.

Professor Ole Andreassen at the NORMENT Centre at University of Oslo, who also was not involved in the current study, said, “This is a highly exciting study which brings the understanding of the disease mechanisms in schizophrenia to the next level. They harvest the discoveries from the recent huge international gene discovery efforts, and with front line single-cell RNA sequencing, they provide novel insight into functional neuronal consequences of all the common gene variants associated with schizophrenia.”