Functional impact of global rare copy number variation in autism spectrum disorders.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

A genome-wide scan for common alleles affecting risk for autism.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Affective-motivational brain responses to direct gaze in children with autism spectrum disorder.

BACKGROUND: It is unclear why children with autism spectrum disorders (ASD) tend to be inattentive to, or even avoid eye contact. The goal of this study was to investigate affective-motivational brain responses to direct gaze in children with ASD. To this end, we combined two measurements: skin conductance responses (SCR), a robust arousal measure, and asymmetry in frontal electroencephalography (EEG) activity which is associated with motivational approach and avoidance tendencies. We also explored whether degree of eye openness and face familiarity modulated these responses. METHODS: Skin conductance responses and frontal EEG activity were recorded from 14 children with ASD and 15 typically developing children whilst they looked at familiar and unfamiliar faces with eyes shut, normally open or wide-open. Stimuli were presented in such a way that they appeared to be looming towards the children. RESULTS: In typically developing children, there were no significant differences in SCRs between the different eye conditions, whereas in the ASD group the SCRs were attenuated to faces with closed eyes and increased as a function of the degree of eye openness. In both groups, familiar faces elicited marginally greater SCRs than unfamiliar faces. In typically developing children, normally open eyes elicited greater relative left-sided frontal EEG activity (associated with motivational approach) than shut eyes and wide-open eyes. In the ASD group, there were no significant differences between the gaze conditions in frontal EEG activity. CONCLUSIONS: Collectively, the results replicate previous finding in showing atypical modulation of arousal in response to direct gaze in children with ASD but do not support the assumption that this response is associated with an avoidant motivational tendency. Instead, children with ASD may lack normative approach-related motivational response to eye contact.

Perceptual Grouping in Autism Spectrum Disorder: An Exploratory Magnetoencephalography Study.

Visual information is organised according to visual grouping principles. In visual grouping tasks individuals with ASD have shown equivocal performance. We explored neural correlates of Gestalt grouping in individuals with and without ASD. Neuromagnetic activity of individuals with (15) and without (18) ASD was compared during a visual grouping task testing grouping by proximity versus similarity. Individuals without ASD showed stronger evoked responses with earlier peaks in response to both grouping types indicating an earlier neuronal differentiation between grouping principles in individuals without ASD. In contrast, individuals with ASD showed particularly prolonged processing of grouping by similarity suggesting a high demand of neural resources. The neuronal processing differences found could explain less efficient grouping performance observed behaviourally in ASD.

Hydroxyzine Use in Preschool Children and Its Effect on Neurodevelopment: A Population-Based Longitudinal Study.

We identified the first-generation antihistamine hydroxyzine as the earliest and most frequently prescribed drug affecting the central nervous system in children under the age of 5 years in the province of British Columbia, Canada (1. 1% prevalence). Whereas, the antagonism of H1-receptors exerts anti-pruritic effects in atopic dermatitis and diaper rash, animal studies suggest an adverse association between reduced neurotransmission of histamine and psychomotor behavior. In order to investigate hydroxyzine safety, we characterized the longitudinal patterns of hydroxyzine use in children under the age of 5 years and determined mental- and psychomotor disorders up to the age of 10 years. We found significantly higher rates of ICD-9 and ICD-10 codes for disorders such as tics (307), anxiety (300) and disturbance of conduct (312) in frequent users of hydroxyzine. Specifically, repeat prescriptions of hydroxyzine compared to a single prescription show an increase in tic disorder, anxiety and disturbance of conduct by odds ratios of: 1.55 (95%CI: 1.23-1.96); 1.34 (95%CI: 1.05-1.70); and 1.34 (95%CI: 1.08-1.66) respectively in children up to the age of 10 years. Furthermore, a non-significant increased trend was found for ADHD (314) and disturbance of emotions (313). This is the first study reporting an association between long-term neurodevelopmental adverse effects and early use of hydroxyzine. Controlled studies are required in order to prove a causal relationship and to confirm the safety of hydroxyzine in the pediatric population. For the time being, we suggest the shortest possible duration for hydroxyzine use in preschool-age children.

Are there theory of mind regions in the brain? A review of the neuroimaging literature.

There have been many functional imaging studies of the brain basis of theory of mind (ToM) skills, but the findings are heterogeneous and implicate anatomical regions as far apart as orbitofrontal cortex and the inferior parietal lobe. The functional imaging studies are reviewed to determine whether the diverse findings are due to methodological factors. The studies are considered according to the paradigm employed (e.g., stories vs. cartoons and explicit vs. implicit ToM instructions), the mental state(s) investigated, and the language demands of the tasks. Methodological variability does not seem to account for the variation in findings, although this conclusion may partly reflect the relatively small number of studies. Alternatively, several distinct brain regions may be activated during ToM reasoning, forming an integrated functional "network." The imaging findings suggest that there are several "core" regions in the network-including parts of the prefrontal cortex and superior temporal sulcus-while several more "peripheral" regions may contribute to ToM reasoning in a manner contingent on relatively minor aspects of the ToM task.

Exploring and building autism service capacity in rural and remote regions: Participatory action research in rural Alberta and British Columbia, Canada.

Based in participatory action research, this project had the aim of building capacity in treatment and support for individuals and families impacted by autism spectrum disorder in remote and rural communities of Canada. Communities were selected based on their rurality and willingness to engage in change efforts for enhanced service delivery within their region. Fifteen discussion groups with key stakeholders were convened in seven communities with ~200 community stakeholders. Based on analyses of these data from the stakeholders, themes were distilled through interpretive description, which in turn were presented to community stakeholders for reflection and collective action. Findings indicate broad thematic domains consisting of: insufficient services, protective factors in community, change efforts via collectivity within community, limitations and benefits of residing in rural communities relative to care associated with autism spectrum disorder, a sense of "community" in rural contexts, and engaging in focused dialogue as a pathway to advancement. Opportunities for building capacity for support in autism spectrum disorder emerged within intersecting layers of leadership, contextual factors, and community collaboration. Consistent with participatory action research principles, emerging local knowledge was supported with strategies for improved autism spectrum disorder service development.

Contextual integration the unusual way: a magnetoencephalographic study of responses to semantic violation in individuals with autism spectrum disorders.

Autism is a neurodevelopmental disorder associated with deficits in language and social communication. Behavioural studies indicate abnormal semantic organization in individuals with autism, but little is known about the neural mechanism underlying the processing of language in context. Magnetoencephalography was used to record neural responses in 11 able adults with autism spectrum disorders reading meaningful sentences and sentences ending with a semantically incongruous word (e.g. 'He sent a photo to the trumpet'). Spatially extended evoked signals at 400 ms (N4) and 750 ms (LPC), as well as synchronized gamma-oscillations, provided clear evidence for specific neuronal processes sensitive to sentence context that differed in individuals with autism compared with typically developing individuals (11 healthy volunteers). Amongst other differences, N4 responses following incongruous words were weaker over left temporal cortices, whereas LPC responses to incongruous words and long-latency gamma-oscillations following congruous words were stronger over central and prefrontal regions in individuals with autism compared with the control group. Also, incongruous words elicited long-lasting gamma-oscillations above 40 Hz in the clinical group, but not in typically developing subjects. These findings may indicate unusual strategies for resolving semantic ambiguity in autism. Moreover, the observed gamma-band responses provide evidence for sustained cortical synchronization across segregated areas in individuals with autism, contrary to claims that a general deficit in either temporal binding or long-range connectivity may explain autism.

SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample.

Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus of candidate gene and association studies. Recently, significant association with autism has been reported for single-nucleotide polymorphisms (SNPs) in the SLC25A12 and CMYA3 genes on chromosome 2q. We attempted to replicate these findings in the collection of families from the International Molecular Genetic Study of Autism Consortium (IMGSAC), using the transmission disequilibrium test and case-control comparison. Our study failed to reveal any significant association for the SNPs tested at either locus, suggesting that these variants are unlikely to play a major role in genetic susceptibility to autism in our sample.

Mutation screening and association analysis of six candidate genes for autism on chromosome 7q.

Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.

New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures.

Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP.

Autism: in search of susceptibility genes.

Autism is a neurodevelopmental disorder of unknown etiology. There is convincing data for the involvement of genetic factors in the development of autism, and the absence of any consistent evidence for an environmental, neuroanatomical, or biochemical cause has led to an increasing number of genetic studies to determine the basis of this complex disorder. The results of recent genetic linkage and candidate gene studies are reviewed in relation to the challenge of clinical and genetic heterogeneity, and prospects for the future of genetic research in autism are considered.

Enhanced access to early visual processing of perceptual simultaneity in autism spectrum disorders.

We compared judgements of the simultaneity or asynchrony of visual stimuli in individuals with autism spectrum disorders (ASD) and typically-developing controls using Magnetoencephalography (MEG). Two vertical bars were presented simultaneously or non-simultaneously with two different stimulus onset delays. Participants with ASD distinguished significantly better between real simultaneity (0 ms delay between two stimuli) and apparent simultaneity (17 ms delay between two stimuli) than controls. In line with the increased sensitivity, event-related MEG activity showed increased differential responses for simultaneity versus apparent simultaneity. The strongest evoked potentials, observed over occipital cortices at about 130 ms, were correlated with performance differences in the ASD group only. Superior access to early visual brain processes in ASD might underlie increased resolution of visual events in perception.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Perception of mirror symmetry in autism spectrum disorders.

Gestalt grouping in autism spectrum disorders (ASD) is selectively impaired for certain organization principles but for not others. Symmetry is a fundamental Gestalt principle characterizing many biological shapes. Sensitivity to symmetry was tested using the Picture Symmetry Test, which requires finding symmetry lines on pictures. Individuals with ASD showed decreased sensitivity to symmetry and a correlation of test performance with performance IQ. Decreased sensitivity for symmetry in ASD is discussed in relation to reduced visual experience of faces in early development.

Enhanced visual temporal resolution in autism spectrum disorders.

Cognitive functions that rely on accurate sequencing of events, such as action planning and execution, verbal and nonverbal communication, and social interaction rely on well-tuned coding of temporal event-structure. Visual temporal event-structure coding was tested in 17 high-functioning adolescents and adults with autism spectrum disorder (ASD) and mental- and chronological-age matched typically-developing (TD) individuals using a perceptual simultaneity paradigm. Visual simultaneity thresholds were lower in individuals with ASD compared to TD individuals, suggesting that autism may be characterised by increased parsing of temporal event-structure, with a decreased capability for integration over time. Lower perceptual simultaneity thresholds in ASD were also related to increased developmental communication difficulties. These results are linked to detail-focussed and local processing bias.

More consistent, yet less sensitive: interval timing in autism spectrum disorders.

Even though phenomenological observations and anecdotal reports suggest atypical time processing in individuals with an autism spectrum disorder (ASD), very few psychophysical studies have investigated interval timing, and the obtained results are contradictory. The present study aimed to clarify which timing processes function atypically in ASD and whether they are related to the ASD diagnostic profile. Visual, auditory, and cross-modal interval timing was assessed in 18 individuals with ASD using a repeated standards version of the temporal generalization task. The use of two different standard durations (600 and 1,000 ms) allowed for an assessment of the scalar property of interval timing in ASD, a fundamental characteristic of interval timing. The ASD group showed clearer adherence to the scalar property of interval timing than the control group. In addition, both groups showed the normal effect that auditory stimuli had longer subjective durations than visual ones. Yet, signal detection analysis showed that the sensitivity of temporal discrimination was reduced in the ASD group across modalities, in particular for auditory standards. Moreover, response criteria in the ASD group were related to symptom strength in the communication domain. The findings suggest that temporal intervals are fundamentally processed in the same way in ASD and TD, but with reduced sensitivity for temporal interval differences in ASD. Individuals with ASD may show a more conservative response strategy due to generally decreased sensitivity for the perception of time intervals.

Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study.

CONTEXT: There is consensus that autism spectrum disorder (ASD) is accompanied by differences in neuroanatomy. However, the neural substrates of ASD during adulthood, as well as how these relate to behavioral variation, remain poorly understood. OBJECTIVE: To identify brain regions and systems associated with ASD in a large, well-characterized sample of adults. DESIGN: Multicenter case-control design using quantitative magnetic resonance imaging. SETTING: Medical Research Council UK Autism Imaging Multicentre Study (MRC AIMS), with sites comprising the Institute of Psychiatry, Kings College London; the Autism Research Centre, University of Cambridge; and the Autism Research Group, University of Oxford. PARTICIPANTS: Eighty-nine men with ASD and 89 male control participants who did not differ significantly in mean age (26 and 28 years, respectively) and full-scale IQ (110 and 113, respectively). MAIN OUTCOME MEASURES: (1) Between-group differences in regional neuroanatomy assessed by voxel-based morphometry and (2) distributed neural systems maximally correlated with ASD, as identified by partial least-squares analysis. RESULTS: Adults with ASD did not differ significantly from the controls in overall brain volume, confirming the results of smaller studies of individuals in this age group without intellectual disability. However, voxelwise comparison between groups revealed that individuals with ASD had significantly increased gray matter volume in the anterior temporal and dorsolateral prefrontal regions and significant reductions in the occipital and medial parietal regions compared with controls. These regional differences in neuroanatomy were significantly correlated with the severity of specific autistic symptoms. The large-scale neuroanatomic networks maximally correlated with ASD identified by partial least-squares analysis included the regions identified by voxel-based analysis, as well as the cerebellum, basal ganglia, amygdala, inferior parietal lobe, cingulate cortex, and various medial, orbital, and lateral prefrontal regions. We also observed spatially distributed reductions in white matter volume in participants with ASD. CONCLUSIONS: Adults with ASD have distributed differences in brain anatomy and connectivity that are associated with specific autistic features and traits. These results are compatible with the concept of autism as a syndrome characterized by atypical neural "connectivity."

Early developmental regression in autism spectrum disorder: evidence from an international multiplex sample.

The characteristics of early developmental regression (EDR) were investigated in individuals with ASD from affected relative pairs recruited to the International Molecular Genetic Study of Autism Consortium (IMGSAC). Four hundred and fifty-eight individuals with ASD were recruited from 226 IMGSAC families. Regression before age 36 months occurred in 23.9% of individuals. The observed concordance rate for EDR within sibling pairs (18.9%) was not significantly above the rate expected under independence (13.5%, p = 0.10). The rate of regression in individuals with ASD from multiplex families was similar to that reported in singleton and epidemiological samples. Regression concordance data were not supportive of a separate familial influence on EDR, other than as a part of autism itself.