Identification And Analysis Of Cell Type-specific Autism-related Gene Modules

Autism Spectrum Disorder(ASD)is a neurodevelopmental disorder that is clinically characterized by difficulties in social interaction and communication,and repetitive and restrictive behaviors.In recent years,the prevalence of ASD has been on the rise.Patients with ASD usually have a poor prognosis and are often unable to work and live independently in their adult years,posing great challenges to public health.Both genetic and environmental factors and their interactions can lead to ASD.The pathogenesis of ASD is extremely complex,and the exact causal mechanism is still poorly understood.Therefore,it is urgent to study the pathogenesis of ASD,which is of great significance to promote the treatment and intervention of ASD.At present,hundreds of risk genes for ASD have been identified based on genetic studies such as GWAS.However,how the disruption of these different genes leads to common clinical phenotypes is still unknown.Understanding the interrelationships among risk genes for ASD and identifying potential shared molecular pathways are essential.Since ASD is believed to be caused by functional abnormalities in brains,the study of functional relationships among ASD risk genes in normal human brains may provide new insights into the converged mechanism of genetic heterogeneity of ASD.The rapid development of single-cell transcriptome sequencing technology has promoted the study of heterogeneous tissues such as human brain.Gene expression levels in individual cells can be quantitatively measured to study inter-cell heterogeneity and to identify cell type-specific gene expression associated with disease etiology.The human brain is a highly heterogeneous organ involving multiple cell types.In different cell types,different genes and/or different functions may be dysregulated in ASD.Although many disease-related genes are expressed in multiple cell types,pathological variations tend to primarily affect specific cell types.It is likely that disease gene modules,rather than individual disease genes,determine the disease manifestations in different cells.Therefore,the identification of cell type-specific ASDrelated gene modules is of great significance for further understanding the molecular mechanism of ASD.Based on single-cell transcriptomic data of healthy human brains,here two analysis methods are proposed to identify cell type-specific ASD-related gene modules to investigate cell type heterogeneity of ASD.Firstly,gene co-expression network analysis is applied to construct gene modules,and then cell type-specific ASD-related gene modules are identified.Compared with the results of common tool and single nucleus transcriptomic data analysis of ASD,the proposed cell type-specific gene network analysis method is effective,and can be applied to other complex diseases,especially those diseases for which single-cell/nucleus transcriptomic data of affected individuals has not yet been available.Then,based on tissue-specific gene networks,cell type-specific gene networks are constructed and then cell type-specific disease gene modules for ASD are identified.Moreover,in order to investigate the effect of genetic overlap between ASD,schizophrenia,and bipolar disorder,the similarities and differences among their cell type-specific disease gene modules are analyzed.For ease of use,an R package named CtsDGM is developed to identify cell type-specific disease gene modules.In this study,two kinds of gene module analysis methods are developed to study the interactions of ASD risk genes,identify cell type-specific gene modules associated with ASD,and analyze the genes and functions affected by ASD in different cell types.The results of this study provide new insights for the study of brain cell type heterogeneity of ASD.