Biology subjects

Baron-Cohen, S.

Publications and source records attributed to Baron-Cohen, S..

10 recordsLinked to original sources

bioRxiv2018

Shared gene co-expression networks in autism from induced pluripotent stem cell (iPSC) neurons

BackgroundAutism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. MethodsIPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation. ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

neuroscience↗

bioRxiv2018

Big data approaches to decomposing heterogeneity across the autism spectrum

Autism is a diagnostic label based on behavior. While the diagnostic criteria attempts to maximize clinical consensus, it also masks a wide degree of heterogeneity between and within individuals at multiple levels of analysis. Understanding this multi-level heterogeneity is of high clinical and translational importance. Here we present organizing principles to frame the work examining multi-level heterogeneity in autism. Theoretical concepts such as spectrum or autisms reflect non-mutually exclusive explanations regarding continuous/dimensional or categorical/qualitative variation between and within individuals. However, common practices of small sample size studies and case-control models are suboptimal for tackling heterogeneity. Big data is an important ingredient for furthering our understanding heterogeneity in autism. In addition to being feature-rich, big data should be both broad (i.e. large sample size) and deep (i.e. multiple levels of data collected on the same individuals). These characteristics help ensure the results from a population are more generalizable and facilitate evaluation of the utility of different models of heterogeneity. A models utility can be shown by its ability to explain clinically or mechanistically important phenomena, but also by explaining how variability manifests across different levels of analysis. The directionality for explaining variability across levels can be bottom-up or top-down, and should include the importance of development for characterizing change within individuals. While progress can be made with supervised models built upon a priori or theoretically predicted distinctions or dimensions of importance, it will become increasingly important to complement such work with unsupervised data-driven discoveries that leverage unknown and multivariate distinctions within big data. Without a better understanding of how to model heterogeneity between autistic people, progress towards the goal of precision medicine may be limited.

neuroscience↗

bioRxiv2018

Genetic contribution to theory of mind in adolescence

Difficulties in theory of mind (the ability to attribute mental states to oneself or others, and to make predictions about anothers behaviour based on these attributions) have been observed in several psychiatric conditions. We investigate the genetic architecture of theory of mind in 4,577 13-year-olds who completed the Emotional Triangles Task (Triangles Task), a first-order test of theory of mind. We observe a small but significant female-advantage on the Triangles Task (Cohens d = 0.19, P < 0.01), in keeping with previous work using other tests of theory of mind. Genome-wide association analyses did not identify any significant loci, and SNP heritability was small and non-significant. Polygenic scores for six psychiatric conditions (ADHD, anorexia, autism, bipolar disorder, depression, and schizophrenia), and empathy were not associated with scores on the Triangles Task. However, polygenic scores of cognitive aptitude, and cognitive empathy, a term synonymous with theory of mind and measured using the \"Reading the Mind in the Eyes\" Test, were significantly associated with scores on the Triangles Task at multiple P-value thresholds, suggesting shared genetics between different measures of theory of mind and cognition.

genetics↗

bioRxiv2018

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sex-specific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.

neuroscience↗

bioRxiv2017

Systemizing is genetically correlated with autism and is genetically distinct from social autistic traits

The core diagnostic criteria for autism comprise two symptom domains - social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, yet, this hypothesis has not been tested using molecular genetics. We test this using a GWAS of a non-social autistic trait, systemizing (N = 51,564), defined as the drive to analyse and build systems. We demonstrate that systemizing is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemizing. Supporting this, polygenic scores for systemizing are significantly positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism.

genetics↗

bioRxiv2017

Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism

Differences in cortical morphology - in particular, cortical volume, thickness and surface area - have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences ({Delta}CT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of {Delta}CT in autism.\n\nWe identify that these genes are enriched for synaptic transmission pathways and explain significant variation in {Delta}CT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected < 10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected < 10-15). We validated the enrichment for downregulated genes in two independent datasets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.

neuroscience↗

bioRxiv2017

Genome-wide association study of social relationship satisfaction: significant loci and correlations with psychiatric conditions

Dissatisfaction in social relationships is reported widely across many psychiatric conditions. We investigated the genetic architecture of family relationship satisfaction and friendship satisfaction in the UK Biobank. We leveraged the high genetic correlation between the two phenotypes (rg = 0.87{+/-}0.03; P < 2.2x10-16) to conduct multi-trait analysis of Genome Wide Association Study (GWAS) (Neffective family = 164,112; Neffective friendship = 158,116). We identified two genome-wide significant associations for both the phenotypes: rs1483617 on chromosome 3 and rs2189373 on chromosome 6, a region previously implicated in schizophrenia. eQTL and chromosome conformation capture in neural tissues prioritizes several genes including NLGN1. Gene-based association studies identified several significant genes, with highest expression in brain tissues. Genetic correlation analysis identified significant negative correlations for multiple psychiatric conditions including highly significant negative correlation with cross-psychiatric disorder GWAS, underscoring the central role of social relationship dissatisfaction in psychiatric diagnosis. The two phenotypes were enriched for genes that are loss of function intolerant. Both phenotypes had modest, significant additive SNP heritability of approximately 6%. Our results underscore the central role of social relationship satisfaction in mental health and identify genes and tissues associated with it.

genomics↗

bioRxiv2017

Structural covariance networks in children with autism or ADHD

While autism and attention-deficit/hyperactivity disorder (ADHD) are considered distinct conditions from a diagnostic perspective, they share some phenotypic features and have high comorbidity. Taking a dual-condition approach might help elucidate shared and distinct neural characteristics.\n\nGraph theory was used to analyse properties of cortical thickness structural covariance networks across both conditions and relative to a neurotypical (NT; n=87) group using data from the ABIDE (autism; n=62) and ADHD-200 datasets (ADHD; n=69). This was analysed in a theoretical framework examining potential differences in long and short range connectivity.\n\nWe found convergence between autism and ADHD, where both conditions show an overall decrease in CT covariance with increased Euclidean distance compared to a neurotypical population. The two conditions also show divergence: less modular overlap between the two conditions than there is between each condition and the neurotypical group. Lastly, the ADHD group also showed reduced wiring costs compared to the autism groups.\n\nOur results indicate a need for taking an integrated approach when considering highly comorbid conditions such as autism and ADHD. Both groups show a distance-covariance relation that more strongly favours short-range over long-range. Thus, on some network features the groups seem to converge, yet on others there is divergence.

neuroscience↗

bioRxiv2016

Genetic overlap between educational attainment, schizophrenia and autism

ImportanceThe genetic relationship between cognition, autism, and schizophrenia is complex. It is unclear how genes that contribute to cognition also contribute to risk for autism and schizophrenia.\n\nObjectiveTo investigate the interaction between genes related to cognition (measured via proxy through educational attainment, which we call edu genes) and genes/biological pathways that are atypical in autism and schizophrenia.\n\nDesignGenetic correlation and enrichment analysis were conducted to identify the interaction between edu genes and risk genes and biological pathways for autism or schizophrenia.\n\nResultsFirst, edu genes are enriched in a specific developmental co-expression module that is also enriched for high confidence autism risk genes. Second, modules enriched for genes that are dysregulated in autism and schizophrenia are also enriched for edu genes. Finally, genes that overlap between the two above modules and educational attainment are significantly enriched for genes that flank human accelerated regions, suggesting increased positive selection for the overlapping gene sets.\n\nConclusionOur results identify distinct co-expression modules where risk genes for the two psychiatric conditions interact with edu genes. This suggests specific pathways that contribute to both cognitive deficits and cognitive talents, in individuals with schizophrenia or autism.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSHow do genes for educational attainment interact with risk genes for autism and schizophrenia?\n\nFindingsWe show that genes for educational attainment (edu genes) are significantly likely to be mutated in autism and intellectual disability. We further show that edu genes also interact with co-expression modules that are associated with autism or schizophrenia and are enriched for differentially expressed genes in autism or schizophrenia. Finally, we identify that the enrichment between risk genes for autism and schizophrenia and human accelerated regions are driven, in part, by their overlap with edu genes.\n\nMeaningEdu genes interact with schizophrenia and autism risk genes in specific pathways, contributing to both cognitive deficits and talents.

genetics↗

bioRxiv2016

Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and brain anatomy

We conducted a genome-wide meta-analysis of cognitive empathy using the Reading the Mind in the Eyes Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1,497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study (BLTS). We confirmed a female advantage on the Eyes Test (Cohens d = 0.21, P < 2.2x10-16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta = 1.58 x 10-8). Common single nucleotide polymorphisms (SNPs) explained 5.8% (95% CI: 0.45 - 0.72; P = 1.00 x 10-17) of the total trait variance in both sexes, and we identified a twin heritability of 0.28 (95% CI: 0.13-0.42). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, measures of empathy (the Empathy Quotient), openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude, and show that the genetic determinants of volumes of the dorsal striatum (caudate nucleus and putamen) are positively correlated with the genetic determinants of performance on the Eyes Test.

genetics↗