Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis

Abstract

Multiple genetic factors contribute to the pathogenesis of autism spectrum disorder (ASD), a kind of neurodevelopmental disorder. Genes were usually studied separately for their associations with ASD. However, genes associated with ASD do not act alone but interact with each other in a network module. The identification of these modules is the basis for the systematic understanding of the pathogenesis of ASD. Moreover, ASD is characterized by highly pathogenic heterogeneity, and gene modules associated with ASD are cell-type-specific. In this study, based on the single-nucleus RNA sequencing data of 41 post-mortem tissue samples from the prefrontal cortex and anterior cingulate cortex of 19 ASD patients and 16 control individuals, we applied sparse module activity factorization, a matrix decomposition method consistent with the multi-factor and heterogeneous characteristics of ASD pathogenesis, to identify cell-type-specific gene modules. Then, statistical procedures were performed to detect highly reproducible cell-type-specific ASD-associated gene modules. Through the enrichment analysis of cell markers, 31 cell-type-specific gene modules related to ASD were further screened out. These 31 gene modules are all enriched with curated ASD risk genes. Finally, we utilized the expression patterns of these cell-type-specific ASD-associated gene modules to build predictive models for ASD. The excellent predictive performance also proved the associations between these gene modules and ASD. Our study confirmed the multifactorial and cell-type-specific characteristics of ASD pathogeneses. The results showed that excitatory neurons such as L2/3, L4, and L5/6-CC play essential roles in ASD’s pathogenic processes. We identified the potential ASD target genes that act together in cell-type-specific modules, such as NRG3, KCNIP4, BAI3, PTPRD, LRRTM4, and LINGO2 in the L2/3 gene modules. Our study offers new potential genomic targets for ASD and provides a novel method to study gene modules involved in the pathogenesis of ASD.

Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons

“…The role of LINGO2 in central nervous system functions is not well understood. In addition, copy number variations (CNVs) in the LINGO2 gene have been reported in ASD patients, and genetic analysis using single RNA sequencing data suggested that LINGO2 expression correlates with the clinical severity of ASD [47][48][49]. We also con rmed increased protein expression of Lingo2 in the cell lysates of primary neurons derived from fetuses exposed to maternal VPA administration (Fig.…”

“…Several copy number variations (CNVs) of LINGO2 have been independently reported in individuals with ASD [47,48]. In addition, analysis of RNA sequencing data from individuals with ASD has shown that the clinical severity of ASD correlates with LINGO2 expression [49]. These patient-based ndings suggest that altered LINGO2 expression may contribute to the development of ASD.…”

The Role of Hub and Spoke Regions in Theory of Mind in Early Alzheimer’s Disease and Frontotemporal Dementia

“…The involvement of frontal territories in ToM has also been shown using neurophysiological techniques such as the skin conductance response (SCR) of healthy participants [39], transcranial magnetic stimulation (TMS) [40] and rs-fMRI [41], which provide complementary and confirmatory evidence of the role of frontal circuits on cognitive functioning, depression [42] and social cognition [43]. The impact of the prefrontal cortex in ToM is also supported by the presence of prefrontal abnormalities both in autism and schizophrenia [44,45], as well as by the impact of prefrontal alterations on cognition in Alzheimer's disease [46].…”

LAR Receptor Tyrosine Phosphatase Family in Healthy and Diseased Brain

“…PTPRD mutations have been directly related to neurological disorders such as restless legs syndrome (RLS) ( Schormair et al, 2008 ; Winkelmann et al, 2011 ; Yang et al, 2011 ), obsessive-compulsive disorder (OCD) ( Mattheisen et al, 2015 ; Gazzellone et al, 2016 ), autism spectrum disorders (ASDs) ( Pinto et al, 2010 ; Levy et al, 2011 ; Gai et al, 2012 ; Liu et al, 2016 ; Ji et al, 2021 ), attention deficit and hyperactivity disorder (ADHD) ( Elia et al, 2010 ), schizophrenia ( Li et al, 2018 ), intellectual disabilities ( Choucair et al, 2015 ), bipolar disorder ( Malhotra et al, 2011 ), addictions ( Drgon et al, 2010 ; Johnson et al, 2008 ; Uhl et al, 2008a ; Uhl et al, 2008b ; Uhl et al, 2010 ), and tauopathies such as Alzheimer’s disease (AD) ( Chibnik et al, 2018 ). The main PTPRD genetic alterations observed in patients have been summarized in Table 2 .…”