Genetic and Cortical Cell-Type Liability Architecture of Autism.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism Spectrum Disorders (ASD) are linked to rare genetic variants affecting brain development.
• Previous research focused on limited high-confidence ASD genes, primarily in prenatal neurons.
• Postnatal studies show ASD-associated transcriptional changes in both neurons and glia.

Purpose of the Study:

• To comprehensively map ASD genetic liability across all human prefrontal cortex cell types throughout development.
• To analyze six classes of rare gene-disrupting variants in a large cohort of individuals with and without ASD.
• To integrate genetic liability with cell-type-specific transcriptomic data.

Main Methods:

• Functional genetic burden analysis of 124,416 individuals (ASD probands and family members).
• Examination of rare gene-disrupting variants (Loss-of-Function, de novo, duplications, missense, inherited) across developmental stages and cell types.
• Correlation of genetic liability with transcriptomic data from postmortem ASD brains.

Main Results:

• ASD genetic liability shows a broad, developmentally dynamic architecture across cortical cell types.
• Loss-of-Function and de novo variants are linked to prenatal cell liability.
• Duplications, missense, and inherited variants increase liability in postnatal and glial cells, including microglia.
• Inherited Loss-of-Function variants implicate microglia in ASD liability, supported by brain transcriptomic data.
• Variants disrupting genes differentially expressed in postmortem ASD brains contribute significantly to ASD liability.

Conclusions:

• ASD genetic risk is cell-type and developmentally specific, impacting both prenatal and postnatal stages.
• The study reveals the contribution of glial cells, particularly microglia, to ASD liability.
• An integrative, cell-type-aware framework is proposed for interpreting ASD risk genetics, highlighting convergence between genetic liability and transcriptomic changes.