UCL | May 2018 | Cell types underlying schizophrenia identified
Historically, genetic studies have linked hundreds of genes to schizophrenia, each contributing a small part to the risk of developing the disease. This has made it difficult to design experiments, as 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. Advances in human genetics and single cell transcriptomics have made it possible for disease to be studied in this way.
Now scientists at UCL have been able to combine new maps of all the genes used in different cell types in the brain with detailed lists of the genes associated with schizophrenia, enabling them to identify the types of cells that underlie the disorder (via UCL).
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.”
The full news item is available from UCL
The paper has been published in the journal Nature Genetics
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.
Skene, N. G. et al.| May 2018 | Genetic identification of brain cell types underlying schizophrenia | Nature Genetics | doi:10.1038/s41588-018-0129-5
The article is available for Rotherham NHS staff to request here