Shared and Cell-Type-Specific Gene Expression Patterns Associated With Autism Revealed by Integrative Regularized Non-Negative Matrix Factorization.

Abstract

Human brain-related disorders, such as autism spectrum disorder (ASD), are often characterized by cell heterogeneity, as the cell atlas of brains consists of diverse cell types. There are commonality and specificity in gene expression among different cell types of brains; hence, there may also be commonality and specificity in dysregulated gene expression affected by ASD among brain cells. Moreover, as genes interact together, it is important to identify shared and cell-type-specific ASD-related gene modules for studying the cell heterogeneity of ASD. To this end, we propose integrative regularized non-negative matrix factorization (iRNMF) by imposing a new regularization based on integrative non-negative matrix factorization. Using iRNMF, we analyze gene expression data of multiple cell types of the human brain to obtain shared and cell-type-specific gene modules. Based on ASD risk genes, we identify shared and cell-type-specific ASD-associated gene modules. By analyzing these gene modules, we study the commonality and specificity among different cell types in dysregulated gene expression affected by ASD. The shared ASD-associated gene modules are mostly relevant to the functioning of synapses, while in different cell types, different kinds of gene functions may be specifically dysregulated in ASD, such as inhibitory extracellular ligand-gated ion channel activity in GABAergic interneurons and excitatory postsynaptic potential and ionotropic glutamate receptor signaling pathway in glutamatergic neurons. Our results provide new insights into the molecular mechanism and pathogenesis of ASD. The identification of shared and cell-type-specific ASD-related gene modules can facilitate the development of more targeted biomarkers and treatments for ASD.