scholarly journals Exploring the Pannexin 1 interactome:In silicocross-analyses with postsynaptic proteins and neuropsychiatric disorder susceptibility genes

2019 ◽  
Author(s):  
Simona D Frederiksen ◽  
Leigh E Wicki-Stordeur ◽  
Juan C Sanchez-Arias ◽  
Leigh Anne Swayne
Keyword(s):  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Susceptibility Genes ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Genome Wide Association Studies ◽  
Interacting Proteins ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Pannexin 1

The Pannexin 1 (Panx1) channel-forming protein is enriched in the central nervous system, and has been associated with several critical neurodevelopmental and plasticity functions; these include dendritic spine formation, neuronal network development, synaptic plasticity, and pathological brain states such as ischemia, epilepsy, and neurodegeneration. Despite major advances in understanding the properties and activation modes of Panx1, the Panx1 interactome remains largely uncharacterized. Considering that Panx1 has been implicated in critical neurodevelopmental and neurodegenerative processes and diseases, we investigated the Panx1 interactome (482 Panx1-interacting proteins) identified from mouse N2a cells. These proteins were cross-analyzed with the postsynaptic proteome of the adult mouse brain previously identified by mass spectrometry (LC-MS/MS), and neurodegenerative disease and neurodevelopmental disorder susceptibility genes previously identified by genome-wide association studies (GWAS); and then further investigated using various bioinformatics tools (PANTHER, GO, KEGG and STRING databases). A total of 104 of the Panx1-interacting proteins were located at the postsynapse, and 99 of these formed a 16-cluster protein-protein interaction (PPI) network (hub proteins: Eef2, Rab6A, Ddx39b, Mapk1, Fh1, Ndufv1 et cetera). The cross-analysis led to the discovery of proteins and candidate genes involved in synaptic function and homeostasis. Of particular note, our analyses also revealed that certain Panx1-interacting proteins are implicated in Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia, autism spectrum disorder and epilepsy. Altogether, our work revealed important clues to the role of Panx1 in neuronal function in health and disease by expanding our knowledge of the PPI network of Panx1, and unveiling previously unidentified Panx1-interacting proteins and networks involved in biological processes and disease.

scholarly journals Linking Autism Risk Genes to Disruption of Cortical Development

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2500
Author(s):  
Marta Garcia-Forn ◽  
Andrea Boitnott ◽  
Zeynep Akpinar ◽  
Silvia De Rubeis
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Cortical Development ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genome Wide Association Studies ◽  
Restricted Interests ◽  
Risk Genes ◽  
Whole Exome

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

scholarly journals Deletion Involving the 7q31-32 Band at the CADPS2 Gene Locus in a Patient with Autism Spectrum Disorder and Recurrent Psychotic Syndrome Triggered by Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Paulo André Pera Grabowski ◽  
Alexandre Ferreira Bello ◽  
Diogo Lima Rodrigues ◽  
Murilo José Forbeci ◽  
Vinicius Motter ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Gene Locus ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Language Communication ◽  
And Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impairments in social functioning, language, communication, and behavior. Recent genome-wide association studies show some microdeletions on the 7q31-32 region, including the CADPS2 locus in autistic patients. This paper reports the case of a patient with ASD and recurrent psychotic syndrome, in which a deletion on the 7q31-32 band at the CADPS2 gene locus was evidenced, as well as a brief review of the literature on the CADPS2 gene and its association with ASD.

scholarly journals Multivariate Analysis of Potential Pleiotropic Genes For Breast, Ovarian And Cervical Cancers Using Gene-Based Association Analysis

2021 ◽  
Author(s):  
XiaoCan Jia ◽  
Nian Shi ◽  
Yu Feng ◽  
Huili Zhu ◽  
Yuping Wang ◽  
...  
Keyword(s):  
Network Analysis ◽  
Association Studies ◽  
Statistical Significance ◽  
Enrichment Analysis ◽  
Biological Pathways ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Ppi Network ◽  
Cervical Cancers ◽  
Protein Protein Interaction

Abstract Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery in gynecological malignancies, the single nucleotide polymorphisms (SNPs) identified by this prevailing univariate approach only explain a small percentage of heredity. The extensive previous studies have repeatedly shown breast, ovarian and cervical cancers have common genetic mechanisms and the overlapping pathophysiological pathways. Novel multivariate analytical methods are necessary to identify shared pleiotropic genes. In this study, a total of 40,859 SNPs mapped in 11,597 gene regions were performed to identify potential common variants by using metaCCA and VEGAS2 analysis. Gene enrichment and protein-protein interaction (PPI) network analysis were used to explore potential biological pathways and connectivity. After metaCCA analysis, 4,203 SNPs (P<1.22×10−6) and 1,886 pleotropic gene (P<4.31×10−6) were identified. By screening the results of gene-based P-values, the existence of 3 confirmed pleiotropic genes and 16 novel genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one cancer in the VEGAS2 analysis were identified. The enrichment analysis showed the biological pathways of these genes were mainly enriched in 4 signaling pathways and 11 differentially expressed genes were found to encode interacting proteins in PPI network analysis. Altogether, we identified novel genetic variants of breast, ovarian and cervical cancers and provided evidence of biological functions which developed new insights for the diagnosis and treatment of these cancers.

scholarly journals Environmental Epigenetics of Diesel Particulate Matter Toxicogenomics

2020 ◽  
Vol 17 (20) ◽  
pp. 7386
Author(s):  
Stephanie M. Bilinovich ◽  
Kristy Lewis ◽  
Barbara L. Thompson ◽  
Jeremy W. Prokop ◽  
Daniel B. Campbell
Keyword(s):  
Particulate Matter ◽  
Environmental Factors ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Molecular Networks ◽  
Diesel Particulate Matter ◽  
Genome Wide Association Studies ◽  
Diesel Particulate ◽  
Genetic And Environmental Factors

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disruptions in social communication and behavioral flexibility. Both genetic and environmental factors contribute to ASD risk. Epidemiologic studies indicate that roadway vehicle exhaust and in utero exposure to diesel particulate matter (DPM) are associated with ASD. Using the Comparative Toxicogenomics Database (CTD), we identified genes connected to DPM exposure and ASD, extracted the known enhancers/promoters of the identified genes, and integrated this with Assay for Transposase Accessible Chromatin (ATAC-seq) data from DPM-exposed human neural progenitor cells. Enhancer/promoter elements with significantly different chromosome accessibility revealed enriched DNA sequence motifs with transcription factor binding sites for EGR1. Variant extraction for linkage disequilibrium blocks of these regions followed by analysis through Genome Wide Association Studies (GWAS) revealed multiple neurological trait associations including exploratory eye movement and brain volume measurement. This approach highlights the effects of pollution on the regulatory regions of genes implicated in ASD by genetic studies, indicating convergence of genetic and environmental factors on molecular networks that contribute to ASD. Integration of publicly available data from the CTD, cell culture exposure studies, and phenotypic genetics synergize extensive evidence of chemical exposures on gene regulation for altered brain development.

scholarly journals UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristina Rodriguez-Fontenla ◽  
Angel Carracedo
Keyword(s):  
In Silico ◽  
Association Studies ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Gastrointestinal Symptoms ◽  
Tissue Expression ◽  
Autism Spectrum ◽  
Biological Characterization ◽  
Large Size ◽  
Body Tissues

AbstractAutism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.

scholarly journals Investigation of gene–environment interactions in relation to tic severity

2021 ◽  
Author(s):  
Mohamed Abdulkadir ◽  
Dongmei Yu ◽  
Lisa Osiecki ◽  
Robert A. King ◽  
Thomas V. Fernandez ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Association Studies ◽  
Autism Spectrum ◽  
Environment Interaction ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Linear Regression Models ◽  
Compulsive Disorder ◽  
Gene Environment ◽  
Tic Severity

AbstractTourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

scholarly journals Genomics-driven drug discovery based on disease-susceptibility genes

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Kyuto Sonehara ◽  
Yukinori Okada
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Disease Susceptibility ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Drug Repurposing ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Associations

AbstractGenome-wide association studies have identified numerous disease-susceptibility genes. As knowledge of gene–disease associations accumulates, it is becoming increasingly important to translate this knowledge into clinical practice. This challenge involves finding effective drug targets and estimating their potential side effects, which often results in failure of promising clinical trials. Here, we review recent advances and future perspectives in genetics-led drug discovery, with a focus on drug repurposing, Mendelian randomization, and the use of multifaceted omics data.

scholarly journals Prediction of response to drug therapy in psychiatric disorders

Open Biology ◽  
2018 ◽  
Vol 8 (5) ◽  
pp. 180031 ◽  
Author(s):  
Shani Stern ◽  
Sara Linker ◽  
Krishna C. Vadodaria ◽  
Maria C. Marchetto ◽  
Fred H. Gage
Keyword(s):  
Autism Spectrum Disorder ◽  
Bipolar Disorder ◽  
Major Depression ◽  
Personalized Medicine ◽  
Psychiatric Disorders ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Patient Reported

Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.

scholarly journals Insights into Dyslexia Genetics Research from the Last Two Decades

2021 ◽  
Vol 12 (1) ◽  
pp. 27
Author(s):  
Florina Erbeli ◽  
Marianne Rice ◽  
Silvia Paracchini
Keyword(s):  
Language Disorder ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Twin Studies ◽  
Genome Wide Association Studies ◽  
Genetics Research ◽  
Genome Wide ◽  
Genetic Risks

Dyslexia, a specific reading disability, is a common (up to 10% of children) and highly heritable (~70%) neurodevelopmental disorder. Behavioral and molecular genetic approaches are aimed towards dissecting its significant genetic component. In the proposed review, we will summarize advances in twin and molecular genetic research from the past 20 years. First, we will briefly outline the clinical and educational presentation and epidemiology of dyslexia. Next, we will summarize results from twin studies, followed by molecular genetic research (e.g., genome-wide association studies (GWASs)). In particular, we will highlight converging key insights from genetic research. (1) Dyslexia is a highly polygenic neurodevelopmental disorder with a complex genetic architecture. (2) Dyslexia categories share a large proportion of genetics with continuously distributed measures of reading skills, with shared genetic risks also seen across development. (3) Dyslexia genetic risks are shared with those implicated in many other neurodevelopmental disorders (e.g., developmental language disorder and dyscalculia). Finally, we will discuss the implications and future directions. As the diversity of genetic studies continues to increase through international collaborate efforts, we will highlight the challenges in advances of genetics discoveries in this field.

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