Genetic identification of brain cell types underlying schizophrenia

By N. Skene, J. Bryois, Trygve E Bakken, G. Breen, J. Crowley, Héléna A. Gaspar, P. Giusti-Rodríguez, R. Hodge, Jeremy A. Miller, A. Muñoz-Manchado and 9 more. Nature Genetics, 2017

638 citations recorded by the source corpus.

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. Integration of single-cell RNA sequencing with genome-wide association data implicates specific brain cell types in schizophrenia. Gene sets previously associated with schizophrenia implicate the same cell types, which include pyramidal cells and medium spiny neurons.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dcf5fe034a83eac6827b11753d72f0ff9fccae52

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Molecular Biology

Citations in the corpus

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “This inhibitory neuron–related module is not enriched for common or rare genetic disease–associated variation, although other studies have found enrichment for SCZ GWAS signal among interneuron markers defined in other ways (63).”
Integrative functional genomic analysis of human brain development and neuropsychiatric risks (2018, background): “Similarly confirmatory was the enrichment of SCZ risk genes in cortical excitatory neurons (56), with enrichment also observed in embryonic and/or fetal progenitor cells and adult cortical interneurons.”
Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex (2020, background): “, 2018), isolated nuclei lack the cytoplasmic compartment as well as axons and proximal dendrites, which limits our understanding of gene expression in the cytosol and neuropil (Skene et al., 2018).”