FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders

https://escholarship.org/content/qt7r99g8kg/qt7r99g8kg.pdf?t=pwn1uy

Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

/pdf/single-cell-genomics-identifies-cell-type-specific-molecular-5ejncse0k6.pdf

Single-cell genomics identifies cell type-specific molecular changes in autism.

Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.

/pdf/transcriptome-analysis-reveals-dysregulation-of-innate-4nwlkoom8o.pdf

Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism.

Autism spectrum disorder is a complex disease with a strong genetic basis that remains under-characterized by current genetics studies. Here, the authors use a computational approach based on a human brain-specific gene network to predict autism-associated genes across the genome and further delineate their functional and developmental characteristics.

/pdf/genome-wide-prediction-and-functional-characterization-of-1qass9rf38.pdf

Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder

New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD.

/pdf/sfari-gene-2-0-a-community-driven-knowledgebase-for-the-1zloykh53r.pdf

Tim Wadkins

Papers

SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)