Study maps genetic risk of schizophrenia to specific brain cells

Summary: A new study reveals the complex molecular mechanisms behind schizophrenia by mapping genetic risk factors to specific brain cells. The researchers used comprehensive genetic and cellular analyzes to identify how these genes affect different cell types in the prefrontal cortex.

The results reveal that excitatory neurons are most affected, linking schizophrenia to neurodevelopment and synapse-related pathways. This research paves the way for targeted and personalized treatments for people with schizophrenia.

Highlights:

• Cell type specificity: The study identifies which types of brain cells express schizophrenia risk genes differently, highlighting excitatory neurons as the most affected.
• Implications of the course: Transcriptional changes in these neurons implicate neurodevelopment and synaptic signaling pathways in schizophrenia.
• Personalized treatments: Insights from the study could lead to tailored interventions, thereby improving clinical outcomes for people with schizophrenia.

Source: McLean Hospital

Schizophrenia is a complex illness with variable presentations, and the diverse nature of this mental health disorder has made it particularly difficult to understand the mechanisms underlying the illness and subsequently develop effective treatments.

In a new study, published on May 23, ScienceA team led by McLean Hospital researchers used comprehensive genetic and cellular analyzes to shed new light on the complex molecular mechanisms underlying schizophrenia.

Their new work provides a map of how genes known to increase the risk of schizophrenia affect specific cells in the brain.

“We discovered which cell types differentially express genes associated with schizophrenia risk, what biological functions are affected within these cells, and which transcription factors are important for these changes,” explained the lead and co-corresponding author. , W. Brad Ruzicka MD, PhD, director of the Human Psychopathology Epigenomics Laboratory at McLean Hospital.

“This understanding will help tailor future treatments to specific genes and cell types, as well as individuals with schizophrenia.”

Schizophrenia affects about 24 million people, or 1 in 300 people, worldwide, according to the World Health Organization.

For the new study, a multicenter team of researchers conducted a comprehensive single-cell analysis of transcriptomic changes in the human prefrontal cortex, examining postmortem brain tissue from 140 individuals across two independent cohorts. Their analyzes included more than 468,000 cells.

They discovered unprecedented insights into the cellular basis of schizophrenia, linking genetic risk factors to specific neuronal populations. Specifically, the researchers found that excitatory neurons emerged as the most affected cell group, with transcriptional changes involving neurodevelopment and synapse-related pathways.

Additionally, they found that known genetic risk factors for schizophrenia converge on alterations in specific neuronal populations, highlighting the interplay between rare and common genomic variants.

Through transcriptomic analysis, two distinct subpopulations of individuals with schizophrenia were identified, marked by the expression of specific excitatory and inhibitory neuronal cell states.

The new study suggests potential links between schizophrenia pathology and processes such as neurodevelopment, synaptic signaling and transcriptional regulation, involving key transcriptional regulators associated with both schizophrenia and neurodevelopmental disorders.

The study authors anticipate that insights from this research could pave the way for targeted interventions and personalized treatments for schizophrenia, potentially improving clinical outcomes for people affected by this debilitating and often disabling disorder.

The research team is now working to expand these findings by studying other brain regions and the molecular impact of other psychiatric illnesses such as bipolar disorder.

They are also investigating another dimension of complexity in this system by studying the expression of the gene isoforms involved and how these cell type-specific gene expression changes lead to functional and potentially druggable changes in the protein space.

“This work advances the understanding of the pathophysiology of schizophrenia in more detail both in the complex landscape of brain cells and in the diverse experiences of people with this illness,” said Ruzicka, who is also medical director associate of the Harvard Brain Tissue Resource Center in McLean. , and assistant professor of psychiatry at Harvard Medical School.

“Our increased mechanistic understanding of schizophrenia paves the way for future research aimed at elucidating the genetic and environmental underpinnings of this complex disease so that we can provide better care to our patients. »

Paternity: Besides Ruzicka, McLean’s co-authors include Sivan Subburaju; Daniel Reed Tso; and Makayla Hourihan.

Other co-authors include Shahin Mohammadi; John F. Fullard; Jose Davila Velderrain; Shan Jiang6; Hao-Chih Lee; Jaroslav Bendl; PsychENCODE Consortium, Georgios Voloudakis; Vahram Haroutunian; Gabriel E. Hoffman; Panos Roussos; and Manolis Kellis.

Disclosures: The authors declare no competing interests.

Funding: This work was supported by National Institutes of Health (NIH) grant K08MH109759 to WBR; Wilf Family Foundations at WBR A complete list of grants received by the authors can be found in the study.

About this research news on genetics and schizophrenia

Author: Ryan Jaslow
Source: McLean Hospital
Contact: Ryan Jaslow – McLean Hospital
Picture: Image is credited to Neuroscience News

Original research: Closed access.
“Single-cell multi-cohort dissection of the schizophrenia transcriptome” by W. Brad Ruzicka et al. Science

Abstract

Single-cell multi-cohort dissection of the schizophrenia transcriptome

INTRODUCTION

Population genomics of schizophrenia has identified strong germline genetic associations for this highly heritable disorder, and molecular investigation of postmortem brain samples has demonstrated transcriptomic and epigenomic alterations associated with this disease.

However, identification of the molecular and cellular pathophysiological processes linking etiological risk factors and clinical presentation remains a challenge, in part due to the complex cellular architecture of the brain.

REASONING

Previous work has implicated specific populations of excitatory and inhibitory neurons in the pathophysiology of schizophrenia, but existing large transcriptomic datasets of bulk tissue samples cannot directly assess cell type-specific contributions to disease.

Single-cell RNA sequencing technologies enable genome-wide measurement of gene expression in single cells at high throughput, going beyond bulk tissue measurements to map disease-associated transcriptional changes in discrete cell populations, without bias towards preselected cell types.

Studying disease-associated phenotypic changes in the myriad cell populations of the human brain can produce new insights into the biology of neuropsychiatric diseases.

RESULTS

Using multiplexed mononuclear RNA sequencing, we developed a single-cell resolution transcriptomic atlas of the prefrontal cortex in subjects with and without schizophrenia and present data from 468,727 nuclei isolated from 140 individuals across two cohorts well independently defined and tested.

We identified expression profiles of brain cell types and neuronal subpopulations and systematically characterized schizophrenia-associated transcriptional changes in each.

For completeness, we report independent cohort-specific analyzes and a joint meta-analysis of differential expression across 25 cell types. Using these data, we identified highly cell type-specific and reproducible expression changes, with 6,634 differential expression events affecting 2,455 genes and favoring downregulated gene expression within excitatory neuronal populations. .

We found significant overlap with previously reported changes in overall cortex expression, primarily for excitatory neuronal populations, whereas changes in lower abundance cell types were less effectively captured in tissue-level profiling. . Differentially expressed genes enrich molecular pathways related to neurodevelopment and synapses and point to a regulatory core of coexpressed transcription factors linked to genetic risk variants of schizophrenia and developmental delay.

Transcription factor targeting of schizophrenia differentially expressed genes in neuronal populations was validated with CUT&Tag in neuronal nuclei isolated from human prefrontal cortex.

Furthermore, transcriptional changes and putative upstream regulatory factors were enriched in genes harboring common and rare schizophrenia risk variants, showing that genetic risk variants across the population frequency spectrum tend to to target genes with measurable expression alterations in the excitatory neurons of patients with schizophrenia. .

Finally, the magnitude of transcriptomic change associated with schizophrenia separated two populations of schizophrenic subjects. Transcriptomic heterogeneity within cohorts was associated with specific cellular states shared across multiple neuronal populations, marked by genes related to synaptic function and one-carbon metabolism, suggesting genes characterizing distinct molecular phenotypes of schizophrenia.

CONCLUSION

Our results provide a valuable resource for studying the molecular pathophysiology of schizophrenia at single-cell resolution, providing insight into the preferential dysregulation of certain…