The study, published in Nature Genetics, by researchers at UCL, Karolinska Institutet (Sweden) and University of North Carolina (USA) offers a roadmap for the development of new therapies to target the condition.

“Understanding which cell types are affected in a 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,” said co-lead author Dr Nathan Skene (UCL Institute of Neurology and Karolinska Institutet).

Genetic studies have linked hundreds of genes to schizophrenia, each contributing a small part to the risk of developing the disease. The great abundance of identified genes has made it difficult to design experiments. Scientists have been struggling to understand what is linking the genes together and whether these genes affect the entire brain diffusely or certain components more than others. 

By combining new maps of all the genes used in different cell types in the brain with detailed lists of the genes associated with schizophrenia, scientists in the current study could identify the types of cells that underlie the disorder. The genetics point towards certain cell types – pyramidal cells, medium spiny neurons, and certain interneurons – each of which originates in distinct areas of the brain, being much more implicated than others in contributing to the disorder.

“This study marks a transition in how we 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,” said co-lead author Dr Jens Hjerling-Leffler (Karolinska Institutet).
Co-lead author Professor Patrick Sullivan (Karolinska Institutet and University of North Carolina) added, “One question now is whether these brain cell types are related to the clinical features of schizophrenia. For example, greater dysfunction in one cell type could make treatment response less likely. Dysfunction in a different cell type could increase the chances of long-term cognitive effects. This would have important implications for development of new treatments, as separate drugs may be required for each cell type involved.”

As a result of rapid progress in two separate fields of science – human genetics and single cell transcriptomics – it only recently has become possible to study diseases in this way. In coming years the researchers suggest that the approach should lead to breakthroughs in the biological understanding of other complex disorders such as autism, major depression, and eating disorders.

The study was financed by the Swedish Research Council, StratNeuro, the Wellcome Trust, the Swedish Brain Foundation, the Swiss National Science Foundation, and the US National Institute of Mental Health. Schizophrenia genetic results were generated with support from the Medical Research Council, and funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration (CRESTAR Consortium).

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