Biological Psychiatry : Autism Spectrum Disorder : Mechanisms and Features (Août 2019)

jeudi 15 août 2019

Le numéro d’août 2019 de, Biologial Psychiatry est consacré aux caractéristiques et mécanismes dans les TSA.

1. Wray NR, Yengo L. Assortative Mating in Autism Spectrum Disorder : Toward an Evidence Base From DNA Data, but Not There Yet. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):250-252.

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2. Cheng Y, Jin P. Dysfunction of Habituation Learning : A Novel Pathogenic Paradigm of Intellectual Disability and Autism Spectrum Disorder. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):253-254.

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3. Heuer LS, Croen LA, Jones KL, Yoshida CK, Hansen RL, Yolken R, Zerbo O, DeLorenze G, Kharrazi M, Ashwood P, Van de Water J. An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk : The Early Markers for Autism Study. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):255-264.

Background The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. Methods Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. Results Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39–2.83 ; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. Conclusions Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.

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4. Pain O, Pocklington AJ, Holmans PA, Bray NJ, O’Brien HE, Hall LS, Pardiñas AF, O’Donovan MC, Owen MJ, Anney R. Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):265-273.

Background A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (ncases = 18,381, ncontrols = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). Methods Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression. Results This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability. Conclusions This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.

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5. Chabbert D, Caubit X, Roubertoux PL, Carlier M, Habermann B, Jacq B, Salin P, Metwaly M, Frahm C, Fatmi A, Garratt AN, Severac D, Dubois E, Kerkerian-Le Goff L, Fasano L, Gubellini P. Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder–like Behavior. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):274-285.

Background Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into “when” and “where” TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. Methods We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. Results These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, ∼50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. Conclusions Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

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6. Connolly S, Anney R, Gallagher L, Heron EA. Evidence of Assortative Mating in Autism Spectrum Disorder. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):286-293.

Background Assortative mating is a nonrandom mating system in which individuals with similar genotypes and/or phenotypes mate with one another more frequently than would be expected in a random mating system. Assortative mating has been hypothesized to play a role in autism spectrum disorder (ASD) in an attempt to explain some of the increase in the prevalence of ASD that has recently been observed. ASD is considered to be a heritable neurodevelopmental disorder, but there is limited understanding of its causes. Assortative mating can be explored through both phenotypic and genotypic data, but up until now it has never been investigated through genotypic measures in ASD. Methods We investigated genotypically similar mating pairs using genome-wide single nucleotide polymorphism data on trio families (Autism Genome Project data [1590 parents] and Simons Simplex Collection data [1962 parents]). To determine whether or not an excess in genetic similarity was present, we employed kinship coefficients and examined spousal correlation between the principal components in both the Autism Genome Project and Simons Simplex Collection datasets. We also examined assortative mating using phenotype data on the parents to detect any correlation between ASD traits. Results We found significant evidence of genetic similarity between the parents of ASD offspring using both methods in the Autism Genome Project dataset. In the Simons Simplex Collection, there was also significant evidence of genetic similarity between the parents when explored through spousal correlation. Conclusions This study gives further support to the hypothesis that positive assortative mating plays a role in ASD.

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7. Fenckova M, Blok LER, Asztalos L, Goodman DP, Cizek P, Singgih EL, Glennon JC, IntHout J, Zweier C, Eichler EE, von Reyn CR, Bernier RA, Asztalos Z, Schenck A. Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):294-305.

Background Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype–phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits. Results We identified >100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response. Conclusions Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.

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8. Woo YJ, Kanellopoulos AK, Hemati P, Kirschen J, Nebel RA, Wang T, Bagni C, Abrahams BS. Domain-Specific Cognitive Impairments in Humans and Flies With Reduced CYFIP1 Dosage. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):306-314.

Background Deletions encompassing a four-gene region on chromosome 15 (BP1-BP2 at 15q11.2), seen at a population frequency of 1 in 500, are associated with increased risk for schizophrenia, epilepsy, and other common neurodevelopmental disorders. However, little is known in terms of how these common deletions impact cognition. Methods We used a Web-based tool to characterize cognitive function in a novel cohort of adult carriers and their noncarrier family members. Results from 31 carrier and 38 noncarrier parents from 40 families were compared with control data from 6530 individuals who self-registered on the Lumosity platform and opted in to participate in research. We then examined aspects of sensory and cognitive function in flies harboring a mutation in Cyfip, the homologue of one of the genes within the deletion. For the fly studies, 10 or more groups of 50 individuals per genotype were included. Results Our human studies revealed profound deficits in grammatical reasoning, arithmetic reasoning, and working memory in BP1-BP2 deletion carriers. No such deficits were observed in noncarrier spouses. Our fly studies revealed deficits in associative and nonassociative learning despite intact sensory perception. Conclusions Our results provide new insights into outcomes associated with BP1-BP2 deletions and call for a discussion on how to appropriately communicate these findings to unaffected carriers. Findings also highlight the utility of an online tool in characterizing cognitive function in a geographically distributed population.

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9. Lake EMR, Finn ES, Noble SM, Vanderwal T, Shen X, Rosenberg MD, Spann MN, Chun MM, Scheinost D, Constable RT. The Functional Brain Organization of an Individual Allows Prediction of Measures of Social Abilities Transdiagnostically in Autism and Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):315-326.

Background Autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD) are associated with complex changes as revealed by functional magnetic resonance imaging. To date, neuroimaging-based models are not able to characterize individuals with sufficient sensitivity and specificity. Further, although evidence shows that ADHD traits occur in individuals with autism spectrum disorder, and autism spectrum disorder traits in individuals with ADHD, the neurofunctional basis of the overlap is undefined. Methods Using individuals from the Autism Brain Imaging Data Exchange and ADHD-200, we apply a data-driven, subject-level approach, connectome-based predictive modeling, to resting-state functional magnetic resonance imaging data to identify brain–behavior associations that are predictive of symptom severity. We examine cross-diagnostic commonalities and differences. Results Using leave-one-subject-out and split-half analyses, we define networks that predict Social Responsiveness Scale, Autism Diagnostic Observation Schedule, and ADHD Rating Scale scores and confirm that these networks generalize to novel subjects. Networks share minimal overlap of edges (<2%) but some common regions of high hubness (Brodmann areas 10, 11, and 21, cerebellum, and thalamus). Further, predicted Social Responsiveness Scale scores for individuals with ADHD are linked to ADHD symptoms, supporting the hypothesis that brain organization relevant to autism spectrum disorder severity shares a component associated with attention in ADHD. Predictive connections and high-hubness regions are found within a wide range of brain areas and across conventional networks. Conclusions An individual’s functional connectivity profile contains information that supports dimensional, nonbinary classification in autism spectrum disorder and ADHD. Furthermore, we can determine disorder-specific and shared neurofunctional pathology using our method.

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10. Graciarena M. Cytokines and Chemokines in Novel Roles : Exploring Their Potential as Predictors of Autism Spectrum Disorder. Biological Psychiatry ;2019 (2019/08/15/) ;86(4):e11-e12.

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