scholarly journals Brain-Specific Deletion of GIT1 Impairs Cognition and Alters Phosphorylation of Synaptic Protein Networks Implicated in Schizophrenia Susceptibility

2018 ◽  
Author(s):  
Daniel M. Fass ◽  
Michael C. Lewis ◽  
Rushdy Ahmad ◽  
Matthew J. Szucs ◽  
Qiangge Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Neurodevelopmental Disorders ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Synaptic Proteins ◽  
Interacting Protein ◽  
Risk Genes ◽  
Multiple Loci ◽  
Coding Variants

AbstractDespite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and find that these mice have deficits in fear conditioning learning and spatial memory. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

scholarly journals Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

2021 ◽  
Author(s):  
Lu Qiao ◽  
Le Xu ◽  
Lan Yu ◽  
Julia Wynn ◽  
Rebecca Hernan ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rare Variants ◽  
De Novo ◽  
Disease Genes ◽  
Risk Genes ◽  
Association Analyses ◽  
Significant Enrichment ◽  
Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

scholarly journals Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

2019 ◽  
Author(s):  
Katherine Warre-Cornish ◽  
Leo Perfect ◽  
Roland Nagy ◽  
Matthew J. Reid ◽  
Annett Mueller ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Viral Entry ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Risk Genes ◽  
Maternal Immune Activation ◽  
Pml Bodies ◽  
Induced Pluripotent ◽  
Cellular Phenotypes ◽  
Human Ipsc

AbstractMaternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFNγ), in offspring’s brains play a central role. IFNγ activates an antiviral cellular state, limiting viral entry and replication. In addition, IFNγ has been implicated in brain development. Here, we hypothesise that IFNγ-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFNγ treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFNγ upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFNγ-induced neurite outgrowth requires both PML and MHCI. We also find that IFNγ disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFNγ-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo Creeth ◽  
Hai-Gwo Hwu ◽  
Wei Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

Abstract Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

AbstractGenes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Genetic subtypes, allelic effects, and convergent neurodevelopmental mechanisms

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Maitreya Das ◽  
Santhosh Girirajan
Keyword(s):  
Neurodevelopmental Disorders ◽  
High Throughput Sequencing ◽  
Complex Disease ◽  
Molecular Subtype ◽  
Neurodevelopmental Disorder ◽  
Disease Etiology ◽  
Risk Genes ◽  
Genetic Subtypes ◽  
Risk Variants ◽  
Functional Consequences

AbstractHigh-throughput sequencing of large affected cohorts have helped uncover a plethora of risk genes for complex neurodevelopmental disorders. However, untangling complex disease etiology also involves understanding the functional consequences of these mutations in order to connect risk variants to resulting phenotypes. Here, we highlight the efforts of Mannucci and colleagues to define a novel molecular subtype of neurodevelopmental disorder associated with mutations in DHX30 and characterize location-specific mutational effects in cell culture and zebrafish models.

scholarly journals Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivity and/or Inattention

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 93
Author(s):  
Noèlia Fernàndez-Castillo ◽  
Judit Cabana-Domínguez ◽  
Djenifer B. Kappel ◽  
Bàrbara Torrico ◽  
Heike Weber ◽  
...  
Keyword(s):  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Gene List ◽  
Autism Spectrum ◽  
Mendelian Inheritance ◽  
Common Variants ◽  
Rare Disorders ◽  
Risk Genes ◽  
Complex Disorders ◽  
Mendelian Disorders

Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.

scholarly journals Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

2016 ◽  
Author(s):  
Andrea Ganna ◽  
Giulio Genovese ◽  
Daniel P. Howrigan ◽  
Andrea Byrnes ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
General Population ◽  
Neurodevelopmental Disorders ◽  
Cognitive Abilities ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
P Value ◽  
Sequencing Data ◽  
Whole Exome ◽  
Number Variation

Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1–5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3×10−8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4×10−5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6–9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population

scholarly journals The interface between genetics and psychology: lessons from developmental dyslexia

2015 ◽  
Vol 282 (1806) ◽  
pp. 20143139 ◽  
Author(s):  
D. V. M. Bishop
Keyword(s):  
Cognitive Deficits ◽  
Developmental Dyslexia ◽  
Neurodevelopmental Disorders ◽  
Rare Variants ◽  
Single Gene ◽  
Twin Studies ◽  
Combined Effects ◽  
Poor Reading ◽  
Small Influence ◽  
Clinical Category

Developmental dyslexia runs in families, and twin studies have confirmed that there is a substantial genetic contribution to poor reading. The way in which discoveries in molecular genetics are reported can be misleading, encouraging us to think that there are specific genes that might be used to screen for disorder. However, dyslexia is not a classic Mendelian disorder that is caused by a mutation in a single gene. Rather, like many other common disorders, it appears to involve combined effects of many genes and environmental factors, each of which has a small influence, possibly supplemented by rare variants that have larger effects but apply to only a minority of cases. Furthermore, to see clearer relationships between genotype and phenotype, we may need to move beyond the clinical category of dyslexia to look at underlying cognitive deficits that may be implicated in other neurodevelopmental disorders.

scholarly journals Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study

2020 ◽  
Vol 216 (5) ◽  
pp. 275-279 ◽  
Author(s):  
Claire Foley ◽  
Elizabeth A. Heron ◽  
Denise Harold ◽  
James Walters ◽  
Michael Owen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Small Subset ◽  
Carrier Status ◽  
Discovery Cohort ◽  
Data Set ◽  
Phenotypic Features

BackgroundCopy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.AimsTo determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.MethodLogistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).ResultsIn the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16–34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58–14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28–19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9–86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0–100.0%) for the replication cohort.ConclusionsThese findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.

scholarly journals Interferon-ɣ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression

2021 ◽  
Author(s):  
Adam Pavelinek ◽  
Rugile Matuleviciute ◽  
Laura Sichlinger ◽  
Lucia Dutan Polit ◽  
Nikos Armeniakos ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Synaptic Proteins ◽  
Synapsin I ◽  
Mrna Levels ◽  
Maternal Immune Activation ◽  
Increased Risk

Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-ɣ (IFNɣ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNɣ affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFNɣ exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFNɣ exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFNɣ exposure. This study builds on our previous work by showing that IFNɣ-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.

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