Genetic risk factors for autism are associated with distinct cellular changes

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A collection of papers from the National Institutes of Health (NIH) consortium PsychENCODE Science, scientific progress and Scientific Reports.

PsychENCODE, chaired by a neuroscientist Dr. Daniel Geschwind Researchers at the University of California, Los Angeles (UCLA) have Multi-omics Technology Through these efforts, the initiative aims to improve our understanding of how psychiatric and other neurological disorders arise at a molecular level, by mapping gene regulation in different parts of the brain during neurodevelopment.

“This collection of papers from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship between genetic mechanisms in the brain and disease risk.” Said Quickly.

Publications include work by Geschwind and colleagues applying single-cell genomics to analyze cell type-specific signatures of autism spectrum disorder (ASD).

“Over the past 15 years, epigenetic and transcriptional profiling of postmortem brain samples from multiple psychiatric disorders, including ASD, has revealed underlying molecular differences,” the researchers said. SaidDifferences include upregulation of immune signaling genes, a blunted gene expression signature in the cortex, and downregulation of certain neuronal markers and synaptic genes.

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Historically, bulk sequencing methods have been used in this setting, and while these approaches are insightful, they cannot provide detailed information about the cell-specific changes unique to ASD.

Geschwind and colleagues hypothesized that detailed molecular profiling at the single-cell level could help understand changes in cortical cells in ASD and, when integrated with data on genetic risk factors, could identify molecular changes that drive specific pathways altered in ASD brains.

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Single-cell methods identify distinct cell types in ASD brains

The researchers isolated more than 800,000 nuclei from postmortem brain tissue from 66 individuals aged between 2 and 60 years. Of this cohort, 33 individuals had a lifetime diagnosis of ASD, and 30 were classified as neurotypical and served as controls. All samples were matched for sex, age, and cause of death. Five of the individuals diagnosed with ASD had duplication 15q syndrome, a genetic disorder. Characteristic This is due to severe fine motor delay, autism spectrum disorder, epilepsy, etc.

Single nucleus RNA sequencing (snRNA-seq) and Single nucleus assay for transposase-accessible chromatin and sequencing (snATAC-seq) The samples were then analyzed. “Our approach (on average more than 10,000 cells and 1860 genes per individual) allowed us to identify all 26 major cortical cell types validated in publicly available cortical cell atlases,” the researchers said. Said.

Geschwind and his colleagues identified different cortical cell types in ASD and control samples, including microglia, oligodendrocytes, astrocytes, and blood-brain barrier cells. They describe the changes they observed in the ASD samples as “subtle,” with the most noticeable changes occurring in neurons that connect the right and left hemispheres and provide long-range connections between different brain regions.

Transcription factor networks drive cellular changes in ASD

By integrating cell-specific and spatial transcriptomics data, Geschwind and his colleagues were able to identify the transcription factor networks that drive the cellular changes observed in ASD.

“In contrast to the subtle changes in cellular composition, changes in gene expression in ASD were large, with 2166 genes downregulated and 1319 genes upregulated across 35 cell types, most of which were cell type specific,” the authors explain.

These factors included genes that are common genetic risk factors for ASD, as well as genes that are considered rare.

“These findings provide a powerful and elegant framework for understanding the molecular changes that occur in the brains of people with ASD, in which cell types they occur, and how they relate to brain circuits,” Geschwind said.

Geschwind said the data could provide insight into potential causal mechanisms of ASD and aid in the development of new diagnostic and therapeutic approaches to impact the condition. Approximately 75 million people worldwide.

reference: Wamsley B, Bicks L, Cheng Y, et al. “Single-cell genomics reveals molecular cascades and cell type-specific signatures in ASD.” Science.384(6698):eadh2602.doi: 10.1126/science.adh2602

This article is press release Published by University of California, Los Angeles. Material has been edited for length and content.