Molecular cascades and cell-type specific signatures in ASD revealed by single cell genomics

Wamsley, Brie; Bicks, Lucy; Cheng, Yuyan; Kawaguchi, Riki; Quintero, Diana; Grundman, Jennifer; Liu, Jianyin; Xiao, Shaohua; Hawken, Natalie; Margolis, Michael; Mazariegos, Samantha; Geschwind, Daniel H.

doi:10.1101/2023.03.10.530869

2023

DOI: 10.1101/2023.03.10.530869

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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: Understanding how genetic variation exerts its effects on the human brain in health and disease has been greatly informed by functional genomic characterization. Studies over the last decade have demonstrated robust evidence of convergent transcriptional and epigenetic profiles in post-mortem cerebral cortex from individuals with Autism Spectrum Disorder (ASD). Here, we perform deep single nuclear (sn) RNAseq to elucidate changes in cell composition, cellular transcriptomes and putative candidate drivers assoc… Show more

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Cited by 31 publications

(67 citation statements)

References 84 publications

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“…S5C, table S4). This observation aligns with existing literature, highlighting the complex gene regulation patterns in CPNs during development and their increased susceptibility to neurodevelopmental disorders such as ASD ( 41, 56, 57 ).…”

Section: Resultssupporting

confidence: 91%

Single-Cell full-length Isoform Sequencing Unveils Transcriptional Dysregulation in Autism Spectrum Disorder During Cerebral Cortex Development

Xu

¹

,

Wang

²

,

Hu

³

et al. 2024

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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.

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“…S5C, table S4). This observation aligns with existing literature, highlighting the complex gene regulation patterns in CPNs during development and their increased susceptibility to neurodevelopmental disorders such as ASD ( 41, 56, 57 ).…”

Section: Resultssupporting

confidence: 91%

Single-Cell full-length Isoform Sequencing Unveils Transcriptional Dysregulation in Autism Spectrum Disorder During Cerebral Cortex Development

Xu

¹

,

Wang

²

,

Hu

³

et al. 2024

Preprint

0

Get access via publisher Add to dashboard Cite

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.

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“…Cross-referencing with the SFARI gene database revealed a striking enrichment of syndromic and high confidence ASD risk genes in the synaptic signature of L5 IT neurons. These findings are in line with RNA sequencing studies that find IT neurons to be the most affected cell types in ASD cortex 25,26,68 and suggest altered intracortical processing in ASD 27,69 . Our synaptic compartment-specific proteome data indicates that compared to Sim1-Cre+/PT neurons, excitatory input of Tlx3-Cre+/IT neurons is particularly vulnerable in ASD.…”

Section: Discussionsupporting

confidence: 88%

“…We find a striking enrichment of ASD risk genes in the excitatory postsynaptic proteome of L5 IT neurons, but not of PT neurons. Our findings align with previous studies highlighting the vulnerability of IT neurons in individuals with autism 18–20 . Moreover, our results suggest that the excitatory postsynaptic compartment of L5 IT neurons is notably susceptible in the context of ASD.…”

Section: Introductionsupporting

confidence: 93%

Synaptic Signatures and Disease Vulnerabilities of Layer 5 Pyramidal Neurons

Marcassa

¹

,

Dascenco

²

,

Lorente-Echeverría

³

et al. 2024

Preprint

1

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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

“…Many of the top pathways suggested upregulated transcripts converged on the cellular response to stress, including the unfolded protein response pathway ( Fig. S6g ), as has been observed previously [39]. Many of the top DEGs, driving gene set enrichment, are known to be expressed in the brain and have been implicated in neurodevelopmental syndromes previously (for example, YWHAG [52]; Fig.…”

Section: Resultssupporting

confidence: 71%

“…gray- matter vs. white-matter resident astrocytes or a subset of reactive microglia). While multiple studies have implicated superficial layer excitatory neurons as a nexus of ASD transcriptional dysregulation [14, 39, 44], we extend this work by our data showing that L2 neurons specifically may exhibit the greatest transcriptional changes.…”

Section: Discussionsupporting

confidence: 73%

A Single-Cell Atlas of DNA Methylation in Autism Spectrum Disorder Reveals Distinct Regulatory and Aging Signatures

Eyring

¹

,

Liu

²

,

Elhajjaoui

³

et al. 2025

Preprint

Get access via publisher Add to dashboard Cite

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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