Transcriptomic and genetic analysis suggests a role for mitochondrial dysregulation in schizophrenia

Schizophrenia is an often devastating disorder characterized by persistent and idiopathic cognitive deficits, delusions and hallucinations. Schizophrenia has been associated with impaired nervous system development and an excitation/inhibition imbalance in the prefrontal cortex. On a molecular level, schizophrenia is moderately heritable and genetically complex. Hundreds of risk genes have been identified, spanning a heterogeneous landscape dominated by loci that confer relatively small risk. Bioinformatic analyses of genetic associations point to a limited set of neurons, mainly excitatory cortical neurons, but other analyses suggest the importance of astrocytes and microglia. To understand different cell type roles in schizophrenia and reveal novel cell-type specific aetiologically relevant perturbations in schizophrenia, our study integrated genetic analysis with single nucleus RNA-seq of 536,618 nuclei from postmortem samples of dorsal prefrontal cortex (Brodmann Area 8/9) of 43 cases with schizophrenia and 42 neurotypical controls. We found no significant difference in cell type abundance. Gene expression in excitatory layer 2-3 intra-telencephalic neurons had the greatest number of differentially expressed transcripts and, together with excitatory deep layer intra-telencephalic neurons, conferred most of the genetic risk for schizophrenia. Most differential expression of genes was found in specific cell types and was dominated by down-regulated transcripts. Down-regulated transcripts were enriched in gene sets including transmembrane transport, mitochondrial function, protein folding, and cell-cell signaling whereas up-regulated transcripts were enriched in gene sets related to RNA processing, including RNA splicing in neurons. Co-regulation network analysis identified 40 schizophrenia-relevant programs across 13 cell types. A gene program largely shared between neuronal subtypes, astrocytes, and oligodendrocytes was significantly enriched for schizophrenia risk, supporting an aetiological role for perturbed protein modification, ion transport, and mitochondrial function. These results were largely consistent with cell-type expression quantitative trait locus and transcriptome-wide association analyses. Moreover, single-cell RNA sequencing results, most prominently mitochondrial dysfunction, had multiple points of convergence with proteomic and long-read RNA sequencing results from samples from the same donors. Our study integrates genetic analysis with transcriptomics to reveal novel cell-type specific aetiologically relevant perturbations in schizophrenia.