Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data.

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) involves numerous genes, but the link between genetic variations and diverse symptoms remains unclear.
• Sleep disturbances are common in ASD, and understanding their genetic basis could inform treatment strategies.
• Identifying shared biological mechanisms between ASD and sleep could lead to improved interventions for sleep problems in individuals with ASD.

Purpose of the Study:

• To identify biological mechanisms connecting ASD risk and co-occurring sleep disturbances.
• To analyze whole exome sequence data for protein-damaging variants (PDVs) in genes associated with ASD or sleep duration.
• To investigate the relationship between genetic dysfunction in identified biological processes and sleep duration in individuals with ASD.

Main Methods:

• Whole exome sequencing data from the Simons Simplex Collection (n=2380) were analyzed.
• Protein-damaging variants (PDVs) were predicted in genes linked to ASD or sleep duration.
• A protein-protein interaction network was constructed, and overrepresentation analyses identified enriched biological processes.
• The association between genetic dysfunction scores and parent-reported sleep duration was assessed.

Main Results:

• 29 genes with PDVs were associated with both ASD and sleep duration.
• A network of 108 proteins linked ASD and sleep duration genes with PDVs.
• Cerebral cortex development (GO:0,021,987) was the most overrepresented biological process with evidence of dysfunction.
• Genetic dysfunction in cerebral cortex development was associated with sleep duration, most notably in adolescents (p=4.65×10⁻³).

Conclusions:

• A bioinformatic approach identified a network linking ASD and sleep duration genes, with dysfunction associated with sleep duration.
• Genetic dysfunction in cerebral cortex development may disrupt sleep homeostasis, impacting sleep in individuals with ASD.
• Future research involving functional assessments and objective sleep measurements in adolescents with ASD is recommended for improved treatment development.