MAGI-S

MAGI-S identifies gene modules to dissect the genetic basis of comorbid epilepsy phenotypes within neurodevelopmental disorders by integrating interaction and expression data.

Key Features:

• Seed-centric module construction: Constructs gene modules centered around a seed gene using similarity in protein-protein interactions and co-expression.
• Integration of PPI and co-expression data: Combines protein-protein interaction networks and co-expression profiles to form cohesive modules.
• Selection of high-confidence NDD seed genes: Uses high-confidence neurodevelopmental disorder (NDD) seed genes with varying associations to epilepsy to compare module properties.
• Enrichment assessment: Evaluates modules for enrichment of de novo mutations, NDD-associated genes, and relevant biological functions.
• Pathway-level detection: Identifies pathway enrichments including synaptic transmission, long-term potentiation, calcium signaling, RNA regulation, and chromatin remodeling.
• Mutation and CNV accounting: Accounts for increased rates of de novo non-synonymous mutations and enrichment of copy number variations (CNVs) observed in autism, intellectual disability, developmental disability, and epilepsy.
• Epilepsy-specific network discrimination: Distinguishes modules seeded by genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, KCNB1) from modules seeded by genes weakly or not associated with epilepsy.

Scientific Applications:

• Dissect epilepsy genetics within NDDs: Compare modules seeded by epilepsy-associated versus non-epilepsy-associated NDD genes to elucidate genetic contributors to seizure phenotypes.
• Pathway mechanism identification: Reveal pathway-level mechanisms (synaptic transmission, long-term potentiation, calcium signaling, RNA regulation, chromatin remodeling) linked to different NDD phenotypes.
• Candidate gene and module prioritization: Prioritize genes and modules for follow-up based on enrichment of de novo mutations and NDD-associated gene content.
• Interpretation of mutation burden and CNVs: Interpret increased de novo non-synonymous mutation burden and CNV enrichment across autism, intellectual disability, developmental disability, and epilepsy in a module context.

Methodology:

MAGI-S uses a seed-centric approach that integrates protein-protein interaction networks and co-expression data to construct modules from selected high-confidence NDD seed genes and assesses those modules for enrichment of de novo mutations, NDD-associated genes, and biological functions.