Integrative functional genomics maps synaptic and developmental-regulatory autism risk-gene sets across human cortex

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) risk genes are implicated in synaptic and developmental biology.
• The functional relevance of these gene sets may differ between prenatal and adult cortical development.

Purpose of the Study:

• To investigate whether predefined autism spectrum disorder (ASD) risk gene sets maintain consistent functional meaning across prenatal and adult cortical contexts.
• To define distinct biological layers associated with ASD risk genes in prenatal and adult brain development.

Main Methods:

• Analysis of predefined ASD risk gene sets using developmental and adult transcriptomics data (BrainSpan, single-cell, bulk cohorts).
• Integration with functional annotations (SynGO, Reactome) and interaction networks (STRING).
• Application of advanced statistical modeling, including donor-aware and composition-aware approaches, alongside various control analyses.

Main Results:

• The broad SFARI gene set showed a significant association with adult cortical ASD-control differences, primarily driven by its synaptic component (SynGO).
• This adult synaptic signal remained robust across multiple stringent statistical models and sensitivity analyses.
• In contrast, a mid-prenatal subset of SFARI genes localized to fetal progenitor and chromatin-regulatory functions, lacking a stable adult cortical association.

Conclusions:

• Predefined ASD risk gene sets reveal distinct functional layers: a synaptic layer associated with adult cortical ASD, and a developmental-regulatory layer prominent in mid-prenatal stages.
• These findings highlight the dynamic nature of ASD risk gene function across different developmental time points and brain contexts.