Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders

Ben-David, Eyal; Shifman, Sagiv

doi:10.1371/journal.pgen.1002556

Cited by 139 publications

(118 citation statements)

References 73 publications

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“…Detecting PPI, coexpression, and gene-ontology networks related to neurodevelopmental and neuropsychiatric diseases is an active area of research (Gilman et al 2011;Sakai et al 2011;Voineagu et al 2011;Ben-David and Shifman 2012). MAGI differs from previous approaches in that it simultaneously considers both PPI and coexpression data while trying to cover genes that are enriched in mutations in probands when compared to controls.…”

Section: Discussionmentioning

confidence: 99%

The discovery of integrated gene networks for autism and related disorders

et al. 2014

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Despite considerable genetic heterogeneity underlying neurodevelopmental diseases, there is compelling evidence that many disease genes will map to a much smaller number of biological subnetworks. We developed a computational method, termed MAGI (merging affected genes into integrated networks), that simultaneously integrates protein–protein interactions and RNA-seq expression profiles during brain development to discover “modules” enriched for de novo mutations in probands. We applied this method to recent exome sequencing of 1116 patients with autism and intellectual disability, discovering two distinct modules that differ in their properties and associated phenotypes. The first module consists of 80 genes associated with Wnt, Notch, SWI/SNF, and NCOR complexes and shows the highest expression early during embryonic development (8–16 post-conception weeks [pcw]). The second module consists of 24 genes associated with synaptic function, including long-term potentiation and calcium signaling with higher levels of postnatal expression. Patients with de novo mutations in these modules are more significantly intellectually impaired and carry more severe missense mutations when compared to probands with de novo mutations outside of these modules. We used our approach to define subsets of the network associated with higher functioning autism as well as greater severity with respect to IQ. Finally, we applied MAGI independently to epilepsy and schizophrenia exome sequencing cohorts and found significant overlap as well as expansion of these modules, suggesting a core set of integrated neurodevelopmental networks common to seemingly diverse human diseases.

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Section: Discussionmentioning

confidence: 99%

The discovery of integrated gene networks for autism and related disorders

et al. 2014

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“…Ben David and Shifman applied WGCNA to genetic data provided by the Allen Human Brain Atlas project (http://www.brain-map.org) and were able to identify modules of co-expressed genes that contain the genes potentially related to some forms of ASD. One of the modules contained genes that produce proteins essential for neural plasticity, while the other is enriched in proteins required for synapse formation and function (Ben-David and Shifman 2012a.…”

Section: Asd and Developmental Mechanismsmentioning

confidence: 99%

Autism, Development and Neural Plasticity

Robinson-Agramonte

Fraguela

Bergado-Rosado

2015

Translational Approaches to Autism Spectrum Disorder

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In this chapter, we show evidences derived from carefully designed animal experiments and clinical data, supporting a role of neuroplasticty on the development and physiopathology of autism. Although the exact mode in which genetic and environmental factors interact in various psychiatric conditions, including autism remains largely unclear, a comprehensive understanding of these complex interactions, including the contribution of immune molecules, in the establishment of neuronal connectivity that may drive into phenotypes of autism spectrum disorder (ASD) is of the greatest importance to understand its causes and develop successful strategies to treat and revert its consequences. Available evidence strongly supports the involvement of maladaptive neuroplasticity, mutations, epigenetic modification, and individual miRNA-related pathways in the pathogenesis and pathophysiology of the complex clinical phenotypes that is included in ASD.

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“…Transcription regulation and chromatin remodelling were also implicated in a combined analysis of the genes disrupted by de novo CNV in all 4 published whole exome sequencing studies in ASD using both pathway and network approaches [81]. The same authors investigated the enrichment of rare and common genetic risk factors in ASD in groups of connected genes based on network analyses showing enrichment in neuronal genes, including genes implicated in clathrin-dependent endocytosis fundamental to synaptic vesicle protein internalization [82]. These analyses have been further informed by resources such as the Brain Span project (http://www.brainspan.org/static/home), providing an atlas of the transcriptome over the course of development.…”

Section: Analysis Of Rare Genetic Variants and Chromosomal Rearrangemmentioning

confidence: 99%

“…ASD has proven heritability; see the paper by Chaste and Devlin [this vol., pp. [80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96]. It is a complex genetic disorder, with both rare and common genetic variations contributing to the risk [2].…”

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confidence: 99%

Molecular Pathways in Autistic Spectrum Disorders

Gallagher¹,

Shen²,

Anney³

2015

Autism Spectrum Disorders

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Major advances in neuroscience have highlighted previously elusive molecular pathways for autistic spectrum disorders (ASD) which are essential to the identification of molecular targets for drug discovery. The evidence of the heritability of ASD is now well established, and the last decade brought an exponential rate of discovery in ASD genetics. In particular rare chromosomal structural rearrangements and rare sequence variants have been implicated, with common genetic variation conferring a modest risk. Rare genetic mutations of major effect offer direct targets for the study of underlying molecular mechanisms. Systems biology approaches such as data mining of large genetic data sets in ASD are also used to identify related functional pathways. A greater understanding of the neural mechanisms underpinning ASD is required to determine disrupted developmental processes and how and when pharmacological and behavioural interventions are best initiated. Identification of the disease mechanisms associated with monogenetic neurodevelopmental disorders such as Rett syndrome and fragile X syndrome have led to new molecular targets and potential treatments which have provided optimism for researchers and the ASD community. Taken together, rare and common genetic variations in ASD implicate critical pathways involving chromatin remodelling, synaptogenesis, synapse specialization and intracellular signalling mechanisms. The following chapter will synthesize evidence from a range of sources to illustrate the molecular pathways that appear to be most implicated in ASD, providing potential targets for new drug exploitation. © 2015 S. Karger AG, BaselAutism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders with impaired social communication, language and behaviour. Among the most frequent disabilities of early childhood and adolescence, they persist into adult life with associated economic, social and personal costs [1]. Treatments for ADS are largely behavioural; pharmacological treatments reduce the comorbid symptoms but do not

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Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders

Cited by 139 publications

References 73 publications

The discovery of integrated gene networks for autism and related disorders

The discovery of integrated gene networks for autism and related disorders

Autism, Development and Neural Plasticity

Molecular Pathways in Autistic Spectrum Disorders

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