Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism

By Neelroop Parikshak, Rui Luo, Alice Zhang, H. Won, J. Lowe, Vijayendran Chandran, Steve Horvath, Daniel H. Geschwind. Cell, 2013

1,012 citations recorded by the source corpus.

Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: 1) do these genetic loci converge on specific biological processes, and 2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto co-expression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest translational regulation by FMRP and transcriptional co-regulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a novel biological framework for investigating the pathophysiology of ASD.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/88ac6e0ed254a3fc3759edd1837f4f50cea9a119

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Citations in the corpus

Cell biology of astrocyte-synapse interactions (2017, neutral): “Astrocyte-Synapse Interactions Are Disrupted in Neurodevelopmental Disorders Alteration in synapse formation, synaptic function, and synaptic remodeling has been implicated in a number of neurodevelopmental disorders, including autism spectrum disorder (ASD) (Parikshak et al., 2013).”
Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism (2013, positive): “In this regard, we note the overall similarities between our findings and those reported in the accompanying study by Parikshak et al. (2013) in this issue of Cell, which uses an alternative approach to identify spatial and temporal convergence in genes involved in neurodevelopmental disorders.”
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019, background): “Among these is the fragile X mental retardation 1 gene ( FMR1 ), required for normal cognitive development (Iossifov et al., 2012; Parikshak et al., 2013; Sittler et al., 1996). oASD mice show decreased inclusion rates of a skipped exon in FMR1 (Figure 3F).”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, background): “Comparing our gene modules to previously published candidate ASD gene networks obtained using WGCNA (Parikshak et al., 2013) shows that our M4 strongly overlaps with previously identified M16 (p = 5.”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “Robust WGCNA was performed to identify signed coexpression modules using gene- and isoform-level quantifications separately, after first regressing out all covariates except for the diagnostic group (94).”
A highly conserved program of neuronal microexons is misregulated in autistic brains (2014, background): “A GO analysis of genes with ASD-associated misregulation of microexons reveals significant enrichment of terms related to axonogenesis and synapse biology (Figure 7E), processes that have been previously implicated in autism (Gilman et al., 2011; Parikshak et al., 2013; Voineagu et al., 2011).”
Developmental regulation of human cortex transcription and its clinical relevance at base resolution (2014, neutral): “Our results suggest that many reported differences in expression occurring across birth, and their subsequent association/enrichment in brain disorders 4,6 may be driven principally by changing neuronal phenotypes, rather than by the commonly considered rise of non-neuronal cell types.”