Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Area of Science:

• Genetics
• Neuroscience
• Bioinformatics

Background:

• Gene-gene interactions (epistasis) are crucial for complex traits in model organisms but challenging to detect in human genome-wide studies.
• The Ras/MAPK pathway is implicated in Mendelian disorders with increased autism spectrum disorder (ASD) symptoms (RASopathies).

Purpose of the Study:

• To investigate the contribution of epistasis to autism spectrum disorders (ASDs) in humans using a reverse-pathway genetic approach.
• To identify novel genetic interactions and candidate genes involved in ASD etiology, particularly those interacting with the Ras/MAPK pathway.

Main Methods:

• Enrichment analysis of common single nucleotide polymorphisms (SNPs) in RASopathy genes within existing genome-wide association studies (GWAS) for ASDs.
• Genome-wide screening for gene-gene interactions between RASopathy gene SNPs and other genome-wide SNPs in ASD-affected individuals.
• Genome-wide association study (GWAS) for modifier mapping using quantitative ASD symptom measures in individuals with RASopathies.
• Functional validation of candidate genes, including GPR141, in relevant cell models.

Main Results:

• Common SNPs in RASopathy genes showed significant enrichment for association signals in GWAS for ASDs (P = 0.02).
• Genome-wide screening identified significant pairwise interactions with RASopathy gene SNPs in ASD-affected individuals (P < 2.2 x 10-16).
• A convergent candidate region, containing the gene GPR141, was identified through independent GWAS approaches and showed dysregulation in a RASopathy neural cell line.

Conclusions:

• Orthogonal genetic approaches provide strong evidence for epistasis contributing to ASDs.
• The Ras/MAPK pathway plays a role in idiopathic ASDs, extending beyond RASopathies.
• GPR141 is identified as a convergent candidate gene potentially interacting with the Ras/MAPK pathway in ASD development.