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

• 成果类型: Article
• 署名作者: Wamsley, Brie; Bicks, Lucy; Cheng, Yuyan; Kawaguchi, Riki; Quintero, Diana; Margolis, Michael; Grundman, Jennifer; Liu, Jianyin; Xiao, Shaohua; Hawken, Natalie; Mazariegos, Samantha; Geschwind, Daniel H.
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12225
• DOI: 10.1126/science.adh2602
• 发表日期: 2024-05-24
• 关键词: range functional connectivity; wide association; autism; brain; interneurons; activation; mechanisms; expression; disorders; mutations

摘要

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.