Abstract
BackgroundStudies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development.MethodsFocusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD.ResultsOur analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline.LimitationsWe were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages.ConclusionsOur pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.
Highlights
Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes
Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala
Comparing the snRNA-seq data of human amygdala genes dysregulated in ASD with our human/mouse, we found that two of the 80 genes (GFAP and KCNQ3) had altered expression in individuals with ASD (Table 2 and Fig. 6)
Summary
Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. As defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), autism spectrum disorder (ASD) is characterized by deficits in social communication and repetitive/restrictive behaviors [1]. Despite these two core defining features, phenotypes and comorbidities in individuals with ASD vary widely. While the multigenic basis of non-syndromic cases of ASD is widely accepted, the underlying genetic load carried by each individual differs This genetic load likely represents a combination of both inherited, and to a large extent, de novo mutations [2,3,4,5,6]. Despite an emerging understanding of ASD genetics, the challenge remains how to identify which of these risk genes and mutations are associated with specific core symptoms
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