Science
 2024
DOI: 10.1126/science.adh2602
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Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics

Brie Wamsley
1
,
Lucy Bicks
2
,
Yuyan Cheng
3
et al.

Abstract: Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type–specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay… Show more

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Cited by 83 publications

(36 citation statements)
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“…Using a hypergeometric test, we analyzed the enrichment of iLR-selected gene sets in SFARI for each cell state. The enrichment analysis revealed that IN-PV, L2/3, and L4 had the highest overlap with SFARI genes (Figure 3C), consistent with findings by Velmeshev et al(Velmeshev et al, 2019) and Wamsley et al(Wamsley et al, 2024). These results strongly support the conclusion that iLR can identify small sets of genes with high relevance, in this cases revealing differences between neuronal cell states in ASD vs control brains.…”
Section: Resultssupporting
confidence: 89%
“…GO analysis revealed top terms related to brain and synaptic functions (Figure 3D). For IN-SST cells, synaptic regulation emerged as the most significantly altered term, consistent with (Wamsley et al, 2024). Terms associated with synaptic regulation, maturation, and neurotransmitter regulation were significantly enriched in L2/3, in agreement with (Wamsley et al, 2024); similar agreement was seen for AST-PP, enriching for apoptosis and cytoskeleton development.…”
Section: Resultssupporting
confidence: 79%
“…For IN-SST cells, synaptic regulation emerged as the most significantly altered term, consistent with (Wamsley et al, 2024). Terms associated with synaptic regulation, maturation, and neurotransmitter regulation were significantly enriched in L2/3, in agreement with (Wamsley et al, 2024); similar agreement was seen for AST-PP, enriching for apoptosis and cytoskeleton development. These findings collectively demonstrate the robustness and biological relevance of iLR for identifying gene sets in the context of ASD that can provide valuable insights into underlying molecular mechanisms.…”
Section: Resultssupporting
confidence: 79%
See 2 more Smart Citations
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…Using a hypergeometric test, we analyzed the enrichment of iLR-selected gene sets in SFARI for each cell state. The enrichment analysis revealed that IN-PV, L2/3, and L4 had the highest overlap with SFARI genes (Figure 3C), consistent with findings by Velmeshev et al(Velmeshev et al, 2019) and Wamsley et al(Wamsley et al, 2024). These results strongly support the conclusion that iLR can identify small sets of genes with high relevance, in this cases revealing differences between neuronal cell states in ASD vs control brains.…”
Section: Resultssupporting
confidence: 89%
“…GO analysis revealed top terms related to brain and synaptic functions (Figure 3D). For IN-SST cells, synaptic regulation emerged as the most significantly altered term, consistent with (Wamsley et al, 2024). Terms associated with synaptic regulation, maturation, and neurotransmitter regulation were significantly enriched in L2/3, in agreement with (Wamsley et al, 2024); similar agreement was seen for AST-PP, enriching for apoptosis and cytoskeleton development.…”
Section: Resultssupporting
confidence: 79%
“…For IN-SST cells, synaptic regulation emerged as the most significantly altered term, consistent with (Wamsley et al, 2024). Terms associated with synaptic regulation, maturation, and neurotransmitter regulation were significantly enriched in L2/3, in agreement with (Wamsley et al, 2024); similar agreement was seen for AST-PP, enriching for apoptosis and cytoskeleton development. These findings collectively demonstrate the robustness and biological relevance of iLR for identifying gene sets in the context of ASD that can provide valuable insights into underlying molecular mechanisms.…”
Section: Resultssupporting
confidence: 79%
See 1 more Smart Citation
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…Our results indicate that Chd8 loss of function in the mouse cortex does not result in major expansion or reduction of any of the cell types we identified, supporting that changes in cellular composition may not be a major feature of ASD. This is consistent with a recent study that identified subtle changes in adult brains from persons with ASD compared to controls, primarily involving microglia and astrocytes 87 . However, we note that we may lack power to detect small but biologically significant differences due to the total number of cells and the low representation of some cell types in our dataset.…”
Section: Discussionsupporting
confidence: 92%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…3e). Target genes of BACH1-bound promoters and CTCF-bound distal regulatory regions were supported by the BACH1 and CTCF-regulated gene modules or regulons derived from single-cell RNA-seq data as expected 14 (Methods, Supplementary Figure 6d-e). The lack of significant overlap between target genes of CTCF-bound promoters and the CTCF regulon suggests that CTCF may contribute to the ASD-associated changes in gene expression mainly via decreased binding to distal regulatory regions.…”
Section: Resultssupporting
confidence: 65%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
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