scholarly journals Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

2018 ◽  
Author(s):  
F. Kyle Satterstrom ◽  
Jack A. Kosmicki ◽  
Jiebiao Wang ◽  
Michael S. Breen ◽  
Silvia De Rubeis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Exome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Functional Changes ◽  
Multiple Paths

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

scholarly journals Rare coding variation illuminates the allelic architecture, risk genes, cellular expression patterns, and phenotypic context of autism

2021 ◽  
Author(s):  
Jack M. Fu ◽  
F. Kyle Satterstrom ◽  
Minshi Peng ◽  
Harrison Brand ◽  
Ryan L. Collins ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Allelic Diversity ◽  
Autism Spectrum ◽  
Functional Variation ◽  
Risk Genes ◽  
Missense Variants ◽  
Cellular Expression

Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation contributing risk for ASD and related NDDs. Using an integrative statistical model, we jointly analyzed rare protein-truncating variants (PTVs), damaging missense variants, and copy number variants (CNVs) derived from exome sequencing of 63,237 individuals from ASD cohorts. We discovered 71 genes associated with ASD at a false discovery rate (FDR) ≤ 0.001, a threshold approximately equivalent to exome-wide significance, and 183 genes at FDR ≤ 0.05. Associations were predominantly driven by de novo PTVs, damaging missense variants, and CNVs: 57.4%, 21.2%, and 8.32% of evidence, respectively. Though fewer in number, CNVs conferred greater relative risk than PTVs, and repeat-mediated de novo CNVs exhibited strong maternal bias in parent-of-origin (e.g., 92.3% of 16p11.2 CNVs), whereas all other CNVs showed a paternal bias. To explore how genes associated with ASD and NDD overlap or differ, we analyzed our ASD cohort alongside a developmental delay (DD) cohort from the deciphering developmental disorders study (DDD; n=91,605 samples). We first reanalyzed the DDD dataset using the same models as the ASD cohorts, then performed joint analyses of both cohorts and identified 373 genes contributing to NDD risk at FDR ≤ 0.001 and 662 NDD risk genes at FDR ≤ 0.05. Of these NDD risk genes, 54 genes (125 genes at FDR ≤ 0.05) were unique to the joint analyses and not significant in either cohort alone. Our results confirm overlap of most ASD and DD risk genes, although many differ significantly in frequency of mutation. Analyses of single-cell transcriptome datasets showed that genes associated predominantly with DD were strongly enriched for earlier neurodevelopmental cell types, whereas genes displaying stronger evidence for association in ASD cohorts were more enriched for maturing neurons. The ASD risk genes were also enriched for genes associated with schizophrenia from a separate rare coding variant analysis of 121,570 individuals, emphasizing that these neuropsychiatric disorders share common pathways to risk.

scholarly journals Identification of Autism Risk Genes in a Chinese Cohort via Whole-Exome Sequencing with the Joint Calling Analysis

2020 ◽  
Author(s):  
Bo Yuan ◽  
Peipei Cheng ◽  
Ran Zhang ◽  
Yasong Du ◽  
Zilong Qiu
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
East Asian ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Large Sample Size ◽  
Risk Genes ◽  
Genetic Components ◽  
Whole Exome

Abstract Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation, transcriptional regulation, and chromatin remodeling, have been identified, the genetic analysis on east Asian ASD cohorts in the whole-geome or whole-exome level is still limited(1-5). Here we performed whole-exome sequencing on 168 ASD probands with their unaffected parents of Chinese origin. We applied a joint calling analytical pipeline based on GATK best practices and identified numerous de novo variants including single nucleotide variants (SNVs) and insertion or deletions (INDELs). By querying the Simons foundation autism research initiative (SFARI) gene database, we found that there were potential novel ASD risk genes in East Asian cohorts, which did not exist in European American populations. Furthermore, our analysis pipeline identified de novo copy number variations (CNVs) of known ASD-related gene based on a sufficiently large sample size, validated by quantitative PCR. Our work indicated that there may be differences in potential ASD genetic components existing across different geographical populations, suggesting that genomic analysis over large cohorts are required for each population in order to precisely identify ASD risk genes.

scholarly journals A machine learning approach to predicting autism risk genes: Validation of known genes and discovery of new candidates

2018 ◽  
Author(s):  
Ying Lin ◽  
Anjali M. Rajadhyaksha ◽  
James B. Potash ◽  
Shizhong Han
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Human Brain ◽  
Candidate Genes ◽  
De Novo ◽  
Expression Patterns ◽  
Autism Spectrum ◽  
Gene Expression Patterns ◽  
Risk Genes ◽  
Gene Level

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic basis. The role ofde novomutations in ASD has been well established, but the set of genes implicated to date is still far from complete. The current study employs a machine learning-based approach to predict ASD risk genes using features from spatiotemporal gene expression patterns in human brain, gene-level constraint metrics, and other gene variation features. The genes identified through our prediction model were enriched for independent sets of ASD risk genes, and tended to be differentially expressed in ASD brains, especially in the frontal and parietal cortex. The highest-ranked genes not only included those with strong prior evidence for involvement in ASD (for example,TCF20andFBOX11), but also indicated potentially novel candidates, such asDOCK3,MYCBP2andCAND1, which are all involved in neuronal development. Through extensive validations, we also showed that our method outperformed state-of-the-art scoring systems for ranking ASD candidate genes. Gene ontology enrichment analysis of our predicted risk genes revealed biological processes clearly relevant to ASD, including neuronal signaling, neurogenesis, and chromatin remodeling, but also highlighted other potential mechanisms that might underlie ASD, such as regulation of RNA alternative splicing and ubiquitination pathway related to protein degradation. Our study demonstrates that human brain spatiotemporal gene expression patterns and gene-level constraint metrics can help predict ASD risk genes. Our gene ranking system provides a useful resource for prioritizing ASD candidate genes.

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 Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

2020 ◽  
Author(s):  
Manuel Göpferich ◽  
Nikhil Oommen George ◽  
Ana Domingo Muelas ◽  
Alex Bizyn ◽  
Rosa Pascual ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Single Cell ◽  
Neuronal Differentiation ◽  
Mrna Translation ◽  
Autism Spectrum ◽  
Adult Brain ◽  
Control Of Gene Expression ◽  
Risk Genes

SUMMARYAutism spectrum disorder (ASD) is a neurodevelopmental disease affecting social behavior. Many of the high-confident ASD risk genes relate to mRNA translation. Specifically, many of these genes are involved in regulation of gene expression for subcellular compartmentalization of proteins1. Cis-regulatory motifs that often localize to 3’- and 5’-untranslated regions (UTRs) offer an additional path for posttranscriptional control of gene expression. Alternative cleavage and polyadenylation (APA) affect 3’UTR length thereby influencing the presence or absence of regulatory elements. However, APA has not yet been addressed in the context of neurodevelopmental disorders. Here we used single cell 3’end sequencing to examine changes in 3’UTRs along the differentiation from neural stem cells (NSCs) to neuroblasts within the adult brain. We identified many APA events in genes involved in neurodevelopment, many of them being high confidence ASD risk genes. Further, analysis of 3’UTR lengths in single cells from ASD and healthy individuals detected longer 3’UTRs in ASD patients. Motif analysis of modulated 3’UTRs in the mouse adult neurogenic lineage and ASD-patients revealed enrichment of the cytoplasmic and polyadenylation element (CPE). This motif is bound by CPE binding protein 4 (CPEB4). In human and mouse data sets we observed co-regulation of CPEB4 and the CPEB-binding synaptic adhesion molecule amyloid beta precursor-like protein 1 (APLP1). We show that mice deficient in APLP1 show aberrant regulation of APA, decreased number of neural stem cells, and autistic-like traits. Our findings indicate that APA is used for control of gene expression along neuronal differentiation and is altered in ASD patients.

scholarly journals Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

2021 ◽  
Author(s):  
Xueya Zhou ◽  
Pamela Feliciano ◽  
Tianyun Wang ◽  
Irina Astrovskaya ◽  
Chang Shu ◽  
...  
Keyword(s):  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Full Spectrum ◽  
Risk Genes ◽  
Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

scholarly journals Increased burden of deleterious variants in essential genes in autism spectrum disorder

2016 ◽  
Vol 113 (52) ◽  
pp. 15054-15059 ◽  
Author(s):  
Xiao Ji ◽  
Rachel L. Kember ◽  
Christopher D. Brown ◽  
Maja Bućan
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
De Novo ◽  
Autism Spectrum ◽  
Essential Genes ◽  
Spectrum Disorder ◽  
Model Organisms ◽  
Disease Genes ◽  
Priority List ◽  
Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human 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 Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

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