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Genetic Risk Factors for Autism Linked to Distinct Cellular Changes

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A collection of papers from the National Institutes of Health (NIH) consortium, PsychENCODE, has been published in Science, Science Advances and Scientific Reports.

PsychENCODE, chaired by neuroscientist Dr. Daniel Geschwind from the University of California Los Angeles (UCLA), is using various multiomics techniques to map gene regulation across different parts of the brain throughout neurodevelopment. Through these efforts, the initiative is seeking to enhance our understanding of how psychiatric and other neurological disorders occur at the molecule level.

“This collection of manuscripts from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain,” said Geschwind.

Among the papers is a study by Geschwind and colleagues that applied single-cell genomics to analyze cell type-specific signatures in autism spectrum disorder (ASD).

“Over the past 15 years, epigenetic and transcriptional profiling of postmortem brain samples from multiple psychiatric conditions, including ASD, have revealed robust underlying molecular differences,” the researchers said. Differences include up-regulation of immune signaling genes, blunting of gene expression signatures in the cortex and down-regulation of specific neuronal markers and synaptic genes.

Historically, bulk sequencing methods have been used in this context. While insightful, these approaches fail to provide granular detail on cell-specific changes that are unique to ASD.

Geschwind and colleagues posited that deep molecular profiling at the single-cell level could aid our understanding of changes in cortical cells in ASD and, when integrated with data on genetic risk factors, might identify the molecular changes that drive certain pathways that are altered in ASD brains. 

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Single-cell methods identify cell types that differ in ASD brains

The researchers isolated over 800,000 nuclei from post-mortem brain tissues that belonged to 66 individuals aged 2–60. Among this population, 33 individuals had received an ASD diagnosis during their life and 30 individuals were classified as neurotypical, providing a control group. All samples were matched by sex, age and cause of death. Five of the individuals diagnosed with ASD had 15q duplication syndrome, a genetic disorder that is characterized by gross fine motor delays, ASD and epilepsy.

Single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatic with sequencing (snATAC-seq) analyses were conducted on the samples. “Our approach (on average >10,000 cells per individual and >1860 genes per cell) enabled identification of all 26 major cortical cell types, validated with published cortical cell atlases,” the researchers said.

Geschwind and colleagues identified cortical cell types that differed in ASD samples compared to control, including microglia, oligodendrocytes, astrocytes and blood–brain barrier cells. They describe the changes observed in ASD samples as “subtle”, with the most profound changes occurring in neurons that connect the right and left hemisphere and offer long-range connectivity between different brain areas.

Transcription factor networks drive cellular changes in ASD

Integrating the cell-specific data with spatial transcriptomics data, Geschwind and colleagues could identify transcription factor networks that drive the cellular changes observed in ASD.

“In contrast to the minor changes in cell composition, the changes observed in gene expression in ASD were substantial: 2166 down-regulated and 1319 up-regulated genes across 35 cell types, most of which were cell type specific,” the authors described.

These drivers were particularly enriched in genes that are common genetic risk factors for ASD, and others that are considered rare.

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

The data provide insight into potential causal mechanisms of ASD, Geschwind said, which could support the development of novel diagnostics and therapeutics for the condition that affects ~75 million people globally.

Reference: Wamsley B, Bicks L, Cheng Y, et al. Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics. Science. 384(6698):eadh2602. doi: 10.1126/science.adh2602

This article is a rework of a press release issued by the University of California Los Angeles. Material has been edited for length and content.