1. Molecular cascades and cell type-specific signatures in ASD revealed by single-cell genomics.
- Author
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Wamsley B, Bicks L, Cheng Y, Kawaguchi R, Quintero D, Margolis M, Grundman J, Liu J, Xiao S, Hawken N, Mazariegos S, and Geschwind DH
- Subjects
- Female, Humans, Male, Astrocytes metabolism, Brain metabolism, Chromatin metabolism, Genomics, Interneurons metabolism, Microglia metabolism, Neurons metabolism, Oligodendroglia metabolism, RNA-Seq, Sequence Analysis, RNA, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Autism Spectrum Disorder genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, Single-Cell Analysis, Transcriptome
- 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 for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain.
- Published
- 2024
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