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

Brie Wamsley(University of California, Los Angeles), Lucy Bicks(University of California, Los Angeles), Yuyan Cheng(University of California, Los Angeles), Riki Kawaguchi(University of California, Los Angeles), Diana Quintero(University of California, Los Angeles), Michael Margolis(University of California, Los Angeles), Jennifer Grundman(University of California, Los Angeles), Jianyin Liu(University of California, Los Angeles), Shaohua Xiao(University of California, Los Angeles), Natalie Hawken(University of California, Los Angeles), Samantha Mazariegos(University of California, Los Angeles), Daniel H. Geschwind(University of California, Los Angeles)
Science
May 23, 2024
10.1126/science.adh2602
Cited by 113

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.

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