Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Neuropsychiatric disorders like autism spectrum disorder (ASD) lack clear brain pathologies but show molecular alterations.
• Previous studies indicated ASD involves altered gene expression in cortical association regions.

Purpose of the Study:

• To investigate the extent of transcriptomic and epigenetic changes across the entire cerebral cortex in ASD.
• To determine if molecular pathology in ASD is confined to association areas or more widespread.

Main Methods:

• RNA-sequencing of 725 brain samples from 11 cortical areas in 112 post-mortem individuals (ASD and controls).
• Single-nucleus RNA-sequencing and methylation profiling.
• Analysis of genetic variation (rare and common) in relation to gene expression modules.

Main Results:

• Widespread transcriptomic changes observed across the cortex in ASD, with an anterior-to-posterior gradient.
• Greatest differences were found in primary visual cortex, with attenuated regional transcriptomic distinctions.
• Molecular signature reflects cell-type-specific gene expression changes, particularly in excitatory neurons and glia.
• ASD genetic variations converge in downregulated synaptic signaling and upregulated protein chaperone gene modules.

Conclusions:

• Molecular pathology in ASD is widespread across the cerebral cortex, including primary sensory areas.
• Transcriptomic alterations in ASD involve specific cell types and are influenced by genetic variation.
• Findings challenge the notion that ASD molecular changes are limited to cortical association regions.