Summary: Researchers have identified different neuron types and provided a new list of genes associated with schizophrenia. The findings could pave the way for developing new targeted therapies to treat the condition.
Source: Karolinska Institute.
Scientists at Karolinska Institutet in Sweden and University of North Carolina, USA, have identified the cell types underlying schizophrenia in a new study published in Nature Genetics. The findings offer a roadmap for the development of new therapies to target the condition.
Schizophrenia is an often devastating disorder causing huge human suffering. 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 have 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.
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 being much more implicated than others. One finding was that there appears to be a few major cell types contributing to the disorder, each of which originates in distinct areas of the brain.
“This 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”, says Jens Hjerling-Leffler, research group leader at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, one of the main authors.
The findings offer a roadmap for the development of new therapies.
“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,” says co-main author Patrick Sullivan, Professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and Yeargan Distinguished Professor in the Department of Genetics and Psychiatry at the University of North Carolina.
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.
“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,” says Nathan Skene, Postdoc at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and UCL Institute of Neurology, UK, one of the lead authors.
Funding: 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 Centre, Program Grant and Project Grant, and funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration (CRESTAR Consortium).
The authors report the following potentially competing financial interests. PF Sullivan: Lundbeck (advisory committee). J Hjerling-Leffler: Cartana (Scientific Adviser) and Roche (grant recipient).
Source: Karolinska Institute
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Original Research: Abstract for “Genetic identification of brain cell types underlying schizophrenia” by Nathan G. Skene, Julien Bryois, Trygve E. Bakken, Gerome Breen, James J. Crowley, Héléna A. Gaspar, Paola Giusti-Rodriguez, Rebecca D. Hodge, Jeremy A. Miller, Ana B. Muñoz-Manchado, Michael C. O’Donovan, Michael J. Owen, Antonio F. Pardiñas, Jesper Ryge, James T. R. Walters, Sten Linnarsson, Ed S. Lein, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Patrick F. Sullivan & Jens Hjerling-Leffler in Nature Genetics. Published May 21 2018.
Genetic identification of brain cell types underlying schizophrenia
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the 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. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.