Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons

Wang, Ping; Zhao, Dejian; Lachman, Herbert M.; Zheng, Deyou

doi:10.1038/s41398-017-0058-6

Cited by 48 publications

(31 citation statements)

References 81 publications

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“…The genes associated with human height were downloaded from the study of Lango Allen et al (2010). The gene lists of Autism_KB genes, iPSD, ePSD, and other brain disorder risk genes were downloaded from the study of Wang et al (2018a). Phenotype ontology analysis (Fig.…”

Section: Gene Set Enrichment Analysismentioning

confidence: 99%

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism

Chen

Mai

et al. 2020

Genome Res.

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Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASDassociated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

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Section: Gene Set Enrichment Analysismentioning

confidence: 99%

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism

Chen

Mai

et al. 2020

Genome Res.

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“…Polymorphisms in Dlx1/2 have been linked to autism susceptibility. 72,73 The Dlx target Arx is one of the most frequently mutated genes in X-linked intellectual disability. Mutations of Arx both in rodents and humans also result in infantile spasms, possibly due to reduced inhibition.…”

Section: Dysregulation Of Interneurons In Neurodevelopmental Disordersmentioning

confidence: 99%

Cortical interneuron function in autism spectrum condition

et al. 2018

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Cortical interneurons (INs) are a diverse group of neurons that project locally and shape the function of neural networks throughout the brain. Multiple lines of evidence suggest that a proper balance of glutamate and GABA signaling is essential for both the proper function and development of the brain. Dysregulation of this system may lead to neurodevelopmental disorders, including autism spectrum condition (ASC). We evaluate the development and function of INs in rodent and human models and examine how neurodevelopmental dysfunction may produce core symptoms of ASC. Finding common physiological mechanisms that underlie neurodevelopmental disorders may lead to novel pharmacological targets and candidates that could improve the cognitive and emotional symptoms associated with ASC.

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“…3D). A previous expression weighted cell-type enrichment analysis of a set of 178 AD risk genes using the same data set failed to identify signi cantly enriched cell types [80], likely due to the incomplete list AD risk genes used in that analysis.…”

Section: Discussionmentioning

confidence: 92%

Deep Post-GWAS Analysis Identifies Potential Risk Genes and Causal Variants for Alzheimer’s Disease, Providing New Insights Into Its Disease Mechanisms

WANG

Zhang

Lin

et al. 2020

Preprint

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Background: Alzheimer’s disease (AD) is a genetically complex, multifactorial neurodegenerative disease. It affects more than 45 million people worldwide and currently remains untreatable. Although genome-wide association studies (GWAS) have identified many AD-associated common variants, only about 25 genes are currently known to affect the risk of developing AD, despite its highly polygenic nature. Moreover, the causal variants underlying GWAS AD-association signals remain unknown.Methods: We developed a computational pipeline that integrates 936 AD-associated SNPs, linkage disequilibrium and genomic data from multiple sources – e.g., disease genes databases, functional annotation of genetic variants, GTEx, and the 1000 Genomes Project – to predict both AD risk genes and their causal variants.Results: We identified 342 putative AD risk genes in 203 risk regions spanning 502 AD-associated common variants. 246 AD risk genes have not been identified as AD risk genes by previous GWAS, and 115 of them are outside the risk regions, likely under the regulation of transcriptional regulatory elements contained therein. Even more significantly, for 109 AD risk genes, we predicted 150 causal variants, of both coding and regulatory (in promoters or enhancers) types, and 85 (57%) of them are supported by functional annotation. In-depth functional analyses showed that AD risk genes were overrepresented in AD-related pathways or GO terms – e.g., the complement and coagulation cascade and phosphorylation and activation of immune response – and their expression was relatively enriched in microglia, endothelia, and pericytes of the human brain. We found nine AD risk genes – e.g., IL1RAP, PMAIP1, LAMTOR4 – as predictors for the prognosis of AD survival and genes such as ARL6IP5 with altered network connectivity between AD patients and normal individuals involved in AD progression.Conclusions: Our findings provide novel biological insights into the genetic architecture, expression profiles, functional pathways involved in the AD etiology, and open new strategies for developing therapeutics targeting AD risk genes or causal variants to influence AD pathogenesis.

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Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons

Cited by 48 publications

References 81 publications

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism

Cortical interneuron function in autism spectrum condition

Deep Post-GWAS Analysis Identifies Potential Risk Genes and Causal Variants for Alzheimer’s Disease, Providing New Insights Into Its Disease Mechanisms

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