Simon Wallace

A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p

Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes.

Serotonin transporter (5‐HTT) and γ‐aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families

Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study on the collection of families from the International Molecular Genetic Study of Autism (IMGSA) Consortium, using the transmission disequilibrium test. Two polymorphisms in the 5-HTT gene (a functional insertion-deletion polymorphism in the promoter and a variable number tandem repeat in the second intron) were examined in 90 families comprising 174 affected individuals. Furthermore, seven microsatellite markers spanning the 15q11-q13 region were studied in 94 families with 182 affected individuals. No significant evidence of association or linkage was found at any of the markers tested, indicating that the 5-HTT and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set.

An investigation of basic facial expression recognition in autism spectrum disorders

This study was designed to test three competing hypotheses (impaired configural processing; impaired Theory of Mind; atypical amygdala functioning) to explain the basic facial expression recognition profile of adults with autism spectrum disorders (ASD). In Experiment 1 the Ekman and Friesen (1976) series were presented upright and inverted. Individuals with ASD were significantly less accurate than controls at recognising upright facial expressions of fear, sadness and disgust and their pattern of errors suggested some configural processing difficulties. Impaired recognition of inverted facial expressions suggested some additional difficulties processing the facial features. Unexpectedly, the clinical group misidentified fear as anger. In Experiment 2 feature processing of facial expressions was investigated by presenting stimuli in a piecemeal fashion, starting with either just the eyes or the mouth. Individuals with ASD were impaired at recognising fear from the eyes and disgust from the mouth; they also confused fearful eyes as being angry. The findings are discussed in terms of the three competing hypotheses tested.

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.

Sense of presence and atypical social judgments in immersive virtual environments Responses of adolescents with Autism Spectrum Disorders

Immersive virtual environments (IVEs) are potentially powerful educational resources but their application for children with Autism Spectrum Disorder (ASD) is under researched. This study aimed to answer two research questions: (1) Do children with ASD experience IVEs in different ways to typically developing children given their cognitive, perceptual and sensory differences? and (2) Can an IVE accurately simulate ecologically valid social situations? Ten children with ASD and 14 typically developing (TD) adolescents all aged 12—16 years experienced three different IVEs. They completed self-report questionnaires on their sense of ‘presence’ in the IVEs and rated ‘social attractiveness’ of a virtual character in socially desirable and undesirable scenarios. The children with ASD reported similar levels of presence to their TD peers and no negative sensory experiences. Although TD adolescents rated the socially desirable character as more socially attractive than the undesirable character, adolescents with ASD rated the two characters as equally socially attractive. These findings suggest that children with ASD do not experience IVEs in different ways to their TD counterparts and that the IVEs are realistic enough to simulate authentic social situations. This study paints a very encouraging picture for the potential uses of IVEs in assessing and educating individuals with ASD.

Commentary – bridging the research and practice gap in autism: The importance of creating research partnerships with schools

While the last 10 years have seen a significant increase in research published on early intervention and autism, there is a persistent disconnect between educational research and practice. Governments have invested significant funds in autism education, and a range of approaches have been implemented in schools, but there is limited research exploring whether these educational strategies are effective and a lack of involvement of teaching professionals in the research. Given that the majority of children and young people with autism spend most of their time in school and not in early or specialised intervention programmes, there is a compelling need to conduct better educational research and implement educational interventions in schools. We argue that building collaborative partnerships between researchers and school practitioners is central to achieving improved understanding of, and outcomes for, pupils on the autism spectrum. This commentary offers perspectives from teachers about their experiences of, and priorities for, research, and also presents a model of collaboration between autism school practitioners and researchers, which could support a more integrated approach to research. We reflect on the strengths and challenges of this as well as outcomes achieved so far.

Face and object processing in autism spectrum disorders

The nature and extent of face‐processing impairments in individuals with autism spectrum disorder (ASD) remain contentious. The aim of this research study is to assess the face‐ and object‐processing performance of individuals with ASD compared with typically developing controls. Our hypothesis was that individuals with ASD would be significantly impaired on tests of face processing but show intact object processing. More specifically, we tested two competing hypotheses to explain face‐processing deficits: holistic hypothesis; second‐order configural hypothesis. Twenty‐six able adults with ASD and 26 intelligence quotient‐matched typically developing controls completed two computerized tests of face and object discrimination. In task 1, the first picture (faces or cars) in a pair was presented as quickly as 40 msec to test holistic processing. In task 2, the decision was whether pairs of faces or houses had been altered in terms of the features or the distance between the features (the second‐order configural properties). Individuals with ASD were impaired on all tests of face processing but showed intact object processing and the pattern of findings favored the holistic hypothesis. The heterogeneous pattern of performance in the clinical group showed that some individuals with ASD perform similarly to typically developing individuals in their face‐processing skills, whereas others are more accurate in object processing compared with face processing.

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E−09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E−23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E−04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

A Study of Impaired Judgment of Eye-Gaze Direction and Related Face-Processing Deficits in Autism Spectrum Disorders

The purpose of this study was to examine whether individuals with autism spectrum disorders (ASD) use the same cognitive strategies as typically developing individuals when processing eye-gaze direction. Subjects viewed pictures of whole faces, the eye region alone, and pairs of arrows presented for 40, 70, or 100 ms, and responded according to the direction the eyes were looking or the arrows pointing (left, right, or straight ahead). Experiment 1 demonstrated that typically developing adults (n = 41) were more accurate and showed shorter reaction times when judging direction of averted eye gaze in the context of the whole face than when only the eyes were visible (eye-region-alone condition). Furthermore, in the eye-region-alone condition participants were more accurate and faster at judging direct eye gaze than averted eye gaze. The same task was used in experiment 2 to compare the performance of a group of individuals with ASD (n = 24) with that of a group of IQ-matched typically developing individuals (n = 26). The performance of the control participants was identical to that observed in experiment 1. Individuals with ASD were able to judge eye-gaze direction accurately at short exposure duration; however, they failed to show the typical advantage for judging averted gaze in whole faces and the increased sensitivity to direct gaze in the eye-region-alone condition. The findings are discussed in terms of impairments to discrete gaze-processing and face-processing mechanisms, and the connectivity between these mechanisms.

Face processing abilities in relatives of individuals with ASD

Individuals with an autism spectrum disorder (ASD) show difficulties identifying familiar faces, recognizing emotional expressions and judging eye‐gaze direction. Recent research suggests that relatives of individuals with AS also show impairments in some aspects of face processing but no study has comprehensively assessed the nature and extent of face‐processing difficulties in a group of relatives. This study compared the performance of 22 parents/adult siblings of individuals with ASD (“relatives” group), 26 adults with ASD, and 26 typically developing adults on tasks of face discrimination, facial expression recognition and judging eye‐gaze direction. Relatives of individuals with ASD were less able to discriminate subtle differences between faces than typically developing adults, but were more sensitive to such differences than adults with ASD. Furthermore, relatives were significantly worse at identifying expressions of fear and disgust than typically developing adults and failed to show the typical sensitivity to direct compared with averted eye‐gaze direction—a strikingly similar pattern to that observed in adults with ASD. These findings show that atypical patterns of face processing are found in some relatives of individuals with ASD and suggest that these difficulties may represent a cognitive endophenotype.