Single-nucleus gene and gene set expression-based similarity network fusion identifies autism molecular subtypes

Abstract

Background Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is highly phenotypically and genetically heterogeneous. With the accumulation of biological sequencing data, more and more studies shift to molecular subtype-first approach, from identifying molecular subtypes based on genetic and molecular data to linking molecular subtypes with clinical manifestation, which can reduce heterogeneity before phenotypic profiling. Results In this study, we perform similarity network fusion to integrate gene and gene set expression data of multiple human brain cell types for ASD molecular subtype identification. Then we apply subtype-specific differential gene and gene set expression analyses to study expression patterns specific to molecular subtypes in each cell type. To demonstrate the biological and practical significance, we analyze the molecular subtypes, investigate their correlation with ASD clinical phenotype, and construct ASD molecular subtype prediction models. Conclusions The identified molecular subtype-specific gene and gene set expression may be used to differentiate ASD molecular subtypes, facilitating the diagnosis and treatment of ASD. Our method provides an analytical pipeline for the identification of molecular subtypes and even disease subtypes of complex disorders.

Unraveling the immunogenetic landscape of autism spectrum disorder: a comprehensive bioinformatics approach

“…Although the diagnosis of ASD has posed challenges for an extended period, the existing biomarkers are insufficient to provide personalized gene-level treatment ( 4 , 5 ). However, molecular subtypes could aid in identifying the heterogeneity among ASD patients and facilitating the discovery of targeted therapies for ASD ( 6 ).…”

“…Extensive clinical and animal research indicates a strong correlation between inflammation and mental illnesses as well as neurodegenerative diseases. Furthermore, certain studies indicate that the activation of inflammatory cells is also related to central nervous system disorders ( 3 , 5 , 7 ). The activation of inflammatory cells is associated with various molecular structures, including cell membrane receptors for central nervous system signaling molecules, cell membrane channels, intracellular signal transduction pathways, and activation of intracellular transcription factors ( 8 ).…”