scholarly journals Deep multitask learning of gene risk for comorbid neurodevelopmental disorders

2020 ◽  
Author(s):  
Ilayda Beyreli ◽  
Oguzhan Karakahya ◽  
A. Ercument Cicek
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
Susceptibility Gene ◽  
Autism Spectrum ◽  
Multitask Learning ◽  
Risk Genes ◽  
Risk Prioritization ◽  
Sequencing Studies ◽  
Number Variation ◽  
Spatio Temporal

AbstractAutism Spectrum Disorder (ASD) and Intellectual Disability (ID) are comorbid neurodevelopmental disorders with complex genetic architectures. Despite large-scale sequencing studies only a fraction of the risk genes were identified for both. Here, we present a novel network-based gene risk prioritization algorithm named DeepND that performs cross-disorder analysis to improve prediction power by exploiting the comorbidity of ASD and ID via multitask learning. Our model leverages information from gene co-expression networks that model human brain development using graph convolutional neural networks and learns which spatio-temporal neurovelopmental windows are important for disorder etiologies. We show that our approach substantially improves the state-of-the-art prediction power in both single-disorder and cross-disorder settings. DeepND identifies mediodorsal thalamus and cerebral cortex brain region and infancy to childhood period as the highest neurodevelopmental risk window for both ASD and ID. We observe that both disorders are enriched in transcription regulators. Despite tight regulatory links in between ASD risk genes, such is lacking across ASD and ID risk genes or within ID risk genes. Finally, we investigate frequent ASD and ID associated copy number variation regions and confident false findings to suggest several novel susceptibility gene candidates. DeepND can be generalized to analyze any combinations of comorbid disorders and is released at http://github.com/ciceklab/deepnd.

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals Impact of exposures to persistent endocrine disrupting compounds on the sperm methylome in regions associated with neurodevelopmental disorders

2021 ◽  
Author(s):  
Angela G. Maggio ◽  
Henry T. Shu ◽  
Benjamin I. Laufer ◽  
Hyeyeon Hwang ◽  
Chongfeng Bi ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Environmental Factors ◽  
Neurodevelopmental Disorders ◽  
Endocrine Disrupting Compounds ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Genome Wide ◽  
Endocrine Disrupting ◽  
Pathway Analyses ◽  
Elevated Exposure

AbstractBackgroundAlthough autism spectrum disorder (ASD) is among the most heritable of neurodevelopmental disorders, the rapidly rising prevalence of ASD suggests that environmental factors may interact with genetic risk for ASD. Environmental factors may impact both gene expression and phenotypes in ASD through epigenetic modifications that, in turn, could lead to intergenerational effects influencing risk for ASDs. Endocrine disrupting compounds (EDCs), such as the long-lived organochlorines, are of particular interest with respect to risk for autism because of their ability to interfere with sex hormones that have been implicated in the regulation of RORA, a dysregulated gene in ASD that is a master regulator of many other ASD risk genes.ObjectivesThe specific aims of this study are to: 1) investigate whether high versus low exposures to the persistent organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are associated with differentially methylated regions (DMRs) in sperm from a Faroese cohort whose natural diet of pilot whale meat and blubber exposes them to higher than average levels of organic pollutants; 2) determine if genes associated with DDE DMRs are enriched for ASD risk genes; 3) identify pathways and functions over-represented among genes associated with DMRs.MethodsWhole genome bisulfite sequencing (WGBS) was used to identify genome-wide DMRs in sperm from individuals divided by high and low exposure levels. Gene ontology and pathway analyses were used to determine enrichment in functional relationships to ASD.ResultsGenes in DMRs not only could discriminate between high and low exposures to DDE, but also were enriched in autism risk genes. Gene ontology and pathway analyses of these genes show significant enrichment for neurodevelopmental processes frequently impacted by ASD.ConclusionResults of this study show that elevated exposure to certain organochlorines is associated with genome-wide DNA methylation patterns in sperm affecting genes involved in neurological functions and developmental disorders, including ASD.

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 Early alterations of large-scale brain networks temporal dynamics in young children with autism

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Aurélie Bochet ◽  
Holger Franz Sperdin ◽  
Tonia Anahi Rihs ◽  
Nada Kojovic ◽  
Martina Franchini ◽  
...  
Keyword(s):  
Large Scale ◽  
Developmental Stages ◽  
Temporal Dynamics ◽  
Brain Networks ◽  
Autism Spectrum ◽  
Brain Network ◽  
Clustering Methods ◽  
Early Developmental Stages ◽  
Spatio Temporal ◽  
Early Developmental

AbstractAutism spectrum disorders (ASD) are associated with disruption of large-scale brain network. Recently, we found that directed functional connectivity alterations of social brain networks are a core component of atypical brain development at early developmental stages in ASD. Here, we investigated the spatio-temporal dynamics of whole-brain neuronal networks at a subsecond scale in 113 toddlers and preschoolers (66 with ASD) using an EEG microstate approach. We first determined the predominant microstates using established clustering methods. We identified five predominant microstate (labeled as microstate classes A–E) with significant differences in the temporal dynamics of microstate class B between the groups in terms of increased appearance and prolonged duration. Using Markov chains, we found differences in the dynamic syntax between several maps in toddlers and preschoolers with ASD compared to their TD peers. Finally, exploratory analysis of brain–behavioral relationships within the ASD group suggested that the temporal dynamics of some maps were related to conditions comorbid to ASD during early developmental stages.

Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families

Neurogenetics ◽  
2014 ◽  
Vol 15 (2) ◽  
pp. 117-127 ◽  
Author(s):  
Gerald Egger ◽  
Katharina M. Roetzer ◽  
Abdul Noor ◽  
Anath C. Lionel ◽  
Huda Mahmood ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number Variation ◽  
Copy Number ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Variation Analysis ◽  
Risk Genes ◽  
Copy Number Variation Analysis ◽  
Number Variation

scholarly journals Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
Targeted Sequencing ◽  
Risk Genes

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Quantitative gait assessment in children with 16p11.2 syndrome

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Sylvie Goldman ◽  
Aston K. McCullough ◽  
Sally Dunaway Young ◽  
Carly Mueller ◽  
Adrianna Stahl ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Motor Dysfunction ◽  
Motor Impairments ◽  
Timed Up And Go ◽  
Adaptive Tests ◽  
Double Support ◽  
Percent Time ◽  
Spatio Temporal ◽  
Base Of Support

Abstract Background Neurodevelopmental disorders such as 16p11.2 syndrome are frequently associated with motor impairments including locomotion. The lack of precise measures of gait, combined with the challenges inherent in studying children with neurodevelopmental disorders, hinders quantitative motor assessments. Gait and balance are quantifiable measures that may help to refine the motor phenotype in 16p11.2. The characterization of motor profile is useful to study the trajectories of locomotion performance of children with genetic variants and may provide insights into neural pathway dysfunction based on genotype/phenotype model. Methods Thirty-six children (21 probands with 16p11.2 deletion and duplication mutation and 15 unaffected siblings), with a mean age of 8.5 years (range 3.2–15.4) and 55% male, were enrolled. Of the probands, 23% (n = 6) had a confirmed diagnosis of autism spectrum disorder (ASD) and were all male. Gait assessments included 6-min walk test (6MWT), 10-m walk/run test (10MWR), timed-up-and-go test (TUG), and spatio-temporal measurements of preferred- and fast-paced walking. The Pediatric Evaluation of Disability Inventory-Computer Adaptive Tests (PEDI-CAT), a caregiver-reported functional assessment, was administered. Measures of balance were calculated using percent time in double support and base of support. Analyses of the six children with ASD were described separately. Results Thirty-six participants completed the protocol. Compared with sibling controls, probands had significantly lower scores on the 6MWT (p = 0.04), 10MWR (p = 0.01), and TUG (p = 0.005). Group differences were also identified in base of support (p = 0.003). Probands had significantly lower PEDI-CAT scores in all domains including the mobility scale (p < 0.001). Using age-matched subsamples, the ASD and non-ASD genetic variant groups had larger base of support compared to the controls. In the fast-paced condition, all participants increased their velocity, and there was a corresponding decrease in percent time in double support compared to the preferred-pace condition in all participants. Only the ASD group presented with upper limb arm/hand stereotypies. Conclusions Children with 16p11.2, with and without ASD, present with balance impairment during locomotion activities. Probands performed worse on functional assessments, and quantitative measures revealed differences in base of support. These results highlight the importance of using precise measures to differentiate motor dysfunction in children with neurodevelopmental disorders.

scholarly journals Autism spectrum disorder in a community-based sample with neurodevelopmental problems in Lagos, Nigeria

2017 ◽  
Vol 7 (2) ◽  
Author(s):  
Yewande O. Oshodi ◽  
Andrew T. Olagunju ◽  
Motunrayo A. Oyelohunnu ◽  
Elizabeth A. Campbell ◽  
Charles S. Umeh ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Neurodevelopmental Disorders ◽  
Challenging Behavior ◽  
Large Scale ◽  
Information Dissemination ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Learning Disorders ◽  
Spectrum Disorder ◽  
Community Based

Autism Spectrum Disorder (ASD) is a globally prevalent neurodevelopmental disorder for which early diagnosis and intervention is the mainstay of management. In the African continent, limited data is available regarding the non-clinic based samples. Lack of information available to caregivers and inadequate skilled manpower often limit early detection and access to the few available though under resourced services in the community. Community based screening can be an important drive to create awareness and improve information dissemination regarding services available for those living with this disorder. This is a descriptive cross-sectional study utilizing data obtained from participants of a community-based autism screening exercise. The surveillance exercise was part of the annual Orange Ribbon initiative for autism awareness and screening held in 2014. Data was obtained from 85 participants involved in the Autism Surveillance screening exercise within the Lagos community. Community public service radio announcements state wide and word of mouth were used to invite and enroll eligible participants to the screening and consultation exercise. A second stage screening and a brief sociodemographic questionnaire followed by a third stage clinical interview and evaluation using the Diagnostic and Statistical Manual of Mental Disorders - 5 Edition (DSM 5) were used. Appropriate consultation and referrals to services in the community were given. Participants had a mean age of 7.53 years (SD 4.35). Twenty-nine (34.5%) met the diagnosis of ASD. Other diagnosis included attention deficit hyperactivity disorder (ADHD), language and speech disorder, intellectual disability (8.3%) and learning disorders (9.5%). Main health concerns to caregivers were poor language development in all (100%), of which 11 (40.7%) were non-verbal; gaze avoidance was seen in 14 (48.3%) and challenging behavior in 12 (42.9%). Comorbidities included seizure disorders (3.4%) and ADHD (6.9%). Persons with autism had history of ASD behavior more often when compared to the other neurodevelopmental disorders and these findings were statistically significant. Referrals were given to caregivers to engage in services within the community. As seen in this study, community understanding of ASD is poor in such locations, in which many persons with other neurodevelopmental disorders are often presented as having autism. Caregivers in the study location are distressed by many symptoms associated with autism and their comorbid conditions. Currently there is an evident role for frequent large scale community based screening and autism awareness exercises possibly using inter-sectoral collaboration as a strategy.

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 Early alterations of large-scale brain networks temporal dynamics in young children with autism

2020 ◽  
Author(s):  
Aurélie Bochet ◽  
Holger Franz Sperdin ◽  
Tonia Anahi Rihs ◽  
Nada Kojovic ◽  
Martina Franchini ◽  
...  
Keyword(s):  
Large Scale ◽  
Developmental Stages ◽  
Temporal Dynamics ◽  
Brain Networks ◽  
Autism Spectrum ◽  
Compensatory Mechanism ◽  
Temporal Properties ◽  
Early Developmental Stages ◽  
Spatio Temporal ◽  
Early Developmental

ABSTRACTDisruption of large-scale brain networks is associated with autism spectrum disorders (ASD). Recently, we found that directed functional connectivity alterations of social brain networks are a core component of atypical brain development at early developmental stages in ASD (Sperdin et al., 2018). Here, we investigated the spatio-temporal dynamics of whole-brain neuronal networks at a subsecond scale in 90 toddlers and preschoolers (47 with ASD) using an EEG microstate approach. Results revealed the presence of five microstate classes that best described the entire dataset (labeled as microstate classes A-E). Microstate class C related to the Default Mode Network (DMN) occurred less in children with ASD. Analysis of brain-behavioural relationships within the ASD group suggested that a compensatory mechanism from microstate C was associated with less severe symptoms and better adaptive skills. These results demonstrate that the temporal properties of some specific EEG microstates are altered in ASD at early developmental stages.

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