Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using...

Area of Science:

• Genetics
• Neuroscience
• Systems Biology

Background:

• Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with hundreds of implicated candidate genes, primarily neurotransmission and synaptic (NS) genes.
• The precise genetic architecture and affected biological pathways in ASD remain incompletely understood.
• Understanding the functional impact of genetic variants is crucial for deciphering ASD's etiology.

Purpose of the Study:

• To clarify the biological processes affected by NS gene variants in individuals with ASD.
• To map the global networks connecting these biological processes.
• To identify novel biological pathways implicated in ASD.

Main Methods:

• Curated a list of 1216 NS candidate genes.
• Searched for ultra-rare (UR) loss-of-function (LoF) variants in ASD whole-exome sequencing data (N=3938 cases) and filtered using gnomAD controls (N=60,146).
• Constructed a protein-protein interaction network of NS genes with UR LoF variants, identified communities using the Leiden algorithm, and explored expression enrichment in brain regions.

Main Results:

• Identified 356 variants in 208 genes, with notable UR LoF variants in PDE11A and SYTL3.
• Expression enrichment analysis highlighted subcortical structures, especially the basal ganglia.
• The network analysis revealed seven communities, linking synaptic and neurotransmitter pathways with ubiquitous processes, and uncovered previously unassociated pathways like brain cytochromes P450 and mitochondrial metabolism.

Conclusions:

• ASD involves disruptions in synaptic and neurotransmitter pathways.
• Ubiquitous biological processes, not traditionally associated with ASD, are also implicated.
• This network-based approach provides a more comprehensive understanding of ASD's genetic and biological underpinnings.