Cell-Type-Specific Analysis of Molecular Pathology in Autism Identifies Common Genes and Pathways Affected Across Neocortical Regions

Dmitry Velmeshev, Marco Magistri, Emilia Maria Cristina Mazza, Patrick Lally, Nathalie Khoury, Evan Ross D’Elia, Silvio Bicciato, Mohammad Ali Faghihi

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Despite its heterogeneity, autism is characterized by a defined behavioral phenotype, suggesting that the molecular pathology affects specific neural substrates to cause behavioral dysfunction. Previous studies identified genes dysregulated in autism cortex but did not address their cell-type specificity. Moreover, it is unknown whether there is a core of genes dysregulated across multiple neocortical regions. We applied RNA sequencing to postmortem brain tissue samples from autism patients and neurologically normal controls and combined our data with previously published datasets. We then identified genes, pathways, and alternative splicing events which are dysregulated in five neocortical regions in autism. To gain information about cell-type specificity of the dysregulated genes, we analyzed single-nuclei RNA sequencing data of adult human cortex and intersected cell-type-specific gene signatures with genes dysregulated in autism in specific cortical regions. We found that autism-associated gene expression changes across 4 frontal and temporal cortex regions converge on 27 genes related to immune response and enriched in human astrocytes, microglia, and brain endothelium. Shared splicing changes, however, are found in genes predominantly associated with synaptic function and adult interneurons and projection neurons. Finally, we demonstrate that regions of DNA differentially methylated in autism overlap genes associated with development and enriched in human cortical oligodendrocytes. Our study identifies signatures of autism molecular pathology shared across neocortical regions, as well as neural cell types enriched for common dysregulated genes, thus paving way for assessing cell-type-specific mechanisms of autism pathology.

Original languageEnglish (US)
Pages (from-to)2279-2289
Number of pages11
JournalMolecular Neurobiology
Issue number5
StatePublished - May 1 2020
Externally publishedYes


  • ASD
  • Alternative splicing
  • Autism
  • DNA methylation
  • RNA sequencing
  • Single-cell RNA sequencing

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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