Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism

By A. Willsey, Stephan J Sanders, Mingfeng Li, Shan Dong, Andrew T. N. Tebbenkamp, R. Muhle, Steven K. Reilly, Leon Lin, S. Fertuzinhos, Jeremy A. Miller and 25 more. Cell, 2013

905 citations recorded by the source corpus.

SUMMARY Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD “seed” genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/37350821d59d0b2f476ccacf71b41b2cccaa6e73

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Cognitive Neuroscience

In Genetics

Citations in the corpus

The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016, neutral): “…neurogenesis in prenatal development (from 50–51 pcd [CS 21 or the beginning of the seventh pcw] when immature neurons are first observed in the CP to 191 pcd [27 pcw], when neocortical excitatory neuron generation stops according to the http://translatingtime.org algorithm [Workman et al., 2013]).”
Translation of Genotype to Phenotype by a Hierarchy of Cell Subsystems (2016, background): “MY received first-year support from the University of California San Diego Graduate Training Program in Bioinformatics (T32-GM008806).”
Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016, neutral): “Remarkably, CTX.M24 was significantly enriched for lncRNAs, genes expressed highly during fetal cortical development, and genes harbouring protein-disrupting mutations found in ASD, suggesting that lncRNAs will be important targets for investigation in ASD 10,25 (FDR 0.05, Extended Data Fig.”
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015, background): “A complementary study identified developmental co-expression networks enriched for ASD risk genes seeded around nine genes with the highest ASD association signal from whole-exome sequencing 112 .”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, methodology): “of ASD both individually (Ben-Shalom et al., 2017; Bernier et al., 2014) and en masse (De Rubeis et al., 2014; Ruzzo et al., 2019; Sanders et al., 2015; Willsey et al., 2013).”
Sex/Gender Differences and Autism: Setting the Scene for Future Research (2015, background): “137-139 Studies need to go beyond comparing groups at genetic or environmental levels alone, to investigate how their interplay has a role in producing potentially multiple “ hits ” in the emergence of autism.”