Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition that results in behavioral, social and communication impairments. ASD has a substantial genetic component, with 88–95% trait concordance among monozygotic twins. Efforts to elucidate the causes of ASD have uncovered hundreds of susceptibility loci and candidate genes. However, owing to its polygenic nature and clinical heterogeneity, only a few of these markers represent clear targets for further analyses. In the present study, we used the linkage structure associated with published genetic markers of ASD to simultaneously improve candidate gene detection while providing a means of prioritizing markers of common genetic variation in ASD. We first mined the literature for linkage and association studies of single-nucleotide polymorphisms, copy-number variations and multi-allelic markers in Autism Genetic Resource Exchange (AGRE) families. From markers that reached genome-wide significance, we calculated male-specific genetic distances, in light of the observed strong male bias in ASD. Four of 67 autism-implicated regions, 3p26.1, 3p26.3, 3q25-27 and 5p15, were enriched with differentially expressed genes in blood and brain from individuals with ASD. Of 30 genes differentially expressed across multiple expression data sets, 21 were within 10 cM of an autism-implicated locus. Among them, CNTN4, CADPS2, SUMF1, SLC9A9, NTRK3 have been previously implicated in autism, whereas others have been implicated in neurological disorders comorbid with ASD. This work leverages the rich multimodal genomic information collected on AGRE families to present an efficient integrative strategy for prioritizing autism candidates and improving our understanding of the relationships among the vast collection of past genetic studies.     

Increased serum levels of macrophage migration inhibitory factor in autism spectrum disorders

ObjectiveMacrophage migration inhibitory factor (MIF) has been suggested as a pivotal regulator of innate immunity and inflammatory. The aim of this study was to measure serum circulating levels of MIF in relation to the degree of the severity of autism spectrum disorders (ASD).MethodsOne hundred and two Chinese children with ASD and same their age-sex matched typical development children were included. Concentrations of MIF were tested by Quantikine Human MIF Immunoassay. Serum levels of homocysteine (HCY), C-reactive protein (CRP) and serum Interleukin 6 (IL-6) were also tested. The influence of serum levels of MIF on ASD risk and ASD severity were performed by binary logistic regression analysis.ResultsThe serum levels of MIF in the children with ASD (24.7 ± 08.9 ng/ml) were significantly higher than those of control subjects (18.3 ± 5.5 ng/ml) (t = 6.134, P < 0.001). Levels of MIF increased with increasing severity of ASD as defined by the CARS score (P < 0.001). In multivariate model, MIF was associated with an increased risk of ASD (OR 1.11, 95% CI: 1.05–1.17; P < 0.001). MIF improved the combined model (HCY/CRP/IL-6) to predict ASD (P < 0.001). At admission, 68 children (66.7%) had a severe autism. In these children, the mean serum level of MIF was higher than in those children with mild to moderate autism (28.1 ± 8.5 ng/ml VS. 17.9 ± 4.7 ng/ml; t = 6.482, P < 0.001). In multivariate model, MIF was still associated with an increased risk of severe ASD (OR: 1.15, 95% CI: 1.04–1.19; P < 0.001). MIF improved the combined model (HCY/CRP/IL-6) to predict severe ASD (P < 0.001).ConclusionsThese results identify high serum MIF levels are associated with severity of ASD. Further study is warranted on the precise involvement of MIF in ASD, and the mechanism by which MIF contributes to ASD pathogenesis.     

Obsessive-compulsive symptoms in parents of Tourette syndrome probands and autism spectrum disorder probands

Obsessive-compulsive symptoms (OCS) frequently occur in patients with Tourette syndrome (TS) and autism spectrum disorders (ASD). It has been suggested that genetic factors play a role in the transmission of both TS and ASD and that obsessive-compulsive disorder (OCD) may have some genetic relationship with these disorders. The objective of this study was to explore whether the OCS associated with TS and ASD were found in the parents of TS and ASD probands by comparing them with normal controls. The subjects were parents of 13 TS and 16 ASD probands. All parents underwent an examination for tic symptoms and OCD, and completed the Maudsley Obsessional Compulsive Inventory (MOCI) and State-Trait Anxiety Inventory (STAI). No significant differences were observed in the MOCI and STAI scores among all three groups. However, the MOCI total score was higher in fathers of ASD probands than in male normal controls with a marginal significance. There was a significant tendency for the mean cleaning score of MOCI in fathers of ASD probands to be higher than that in male normal controls, and the mean checking score in fathers of ASD probands was fourfold higher than that in male normal controls, although there was no significant difference. No significant relationship was observed between OCS in TS or ASD probands and OCS of their parents. Further studies on OCD and OCS including a dimensional approach within ASD families are needed.     

Elevated amygdala response to faces and gaze aversion in autism spectrum disorder

Autism spectrum disorders (ASD) are often associated with impairments in judgment of facial expressions. This impairment is often accompanied by diminished eye contact and atypical amygdala responses to face stimuli. The current study used a within-subjects design to examine the effects of natural viewing and an experimental eye-gaze manipulation on amygdala responses to faces. Individuals with ASD showed less gaze toward the eye region of faces relative to a control group. Among individuals with ASD, reduced eye gaze was associated with higher threat ratings of neutral faces. Amygdala signal was elevated in the ASD group relative to controls. This elevated response was further potentiated by experimentally manipulating gaze to the eye region. Potentiation by the gaze manipulation was largest for those individuals who exhibited the least amount of naturally occurring gaze toward the eye region and was associated with their subjective threat ratings. Effects were largest for neutral faces, highlighting the importance of examining neutral faces in the pathophysiology of autism and questioning their use as control stimuli with this population. Overall, our findings provide support for the notion that gaze direction modulates affective response to faces in ASD.     

Structural connectivity of the amygdala in young adults with autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by impairments in social cognition, a function associated with the amygdala. Subdivisions of the amygdala have been identified which show specificity of structure, connectivity, and function. Little is known about amygdala connectivity in ASD. The aim of this study was to investigate the microstructural properties of amygdala—cortical connections and their association with ASD behaviours, and whether connectivity of specific amygdala subregions is associated with particular ASD traits. The brains of 51 high‐functioning young adults (25 with ASD; 26 controls) were scanned using MRI. Amygdala volume was measured, and amygdala—cortical connectivity estimated using probabilistic tractography. An iterative ‘winner takes all’ algorithm was used to parcellate the amygdala based on its primary cortical connections. Measures of amygdala connectivity were correlated with clinical scores. In comparison with controls, amygdala volume was greater in ASD (F(1,94) = 4.19; p = .04). In white matter (WM) tracts connecting the right amygdala to the right cortex, ASD subjects showed increased mean diffusivity (t = 2.35; p = .05), which correlated with the severity of emotion recognition deficits (rho = ?0.53; p = .01). Following amygdala parcellation, in ASD subjects reduced fractional anisotropy in WM connecting the left amygdala to the temporal cortex was associated with with greater attention switching impairment (rho = ?0.61; p = .02). This study demonstrates that both amygdala volume and the microstructure of connections between the amygdala and the cortex are altered in ASD. Findings indicate that the microstructure of right amygdala WM tracts are associated with overall ASD severity, but that investigation of amygdala subregions can identify more specific associations.     

Epilepsy in autism spectrum disorder

The purpose of this review is to provide an overview of the research on epilepsy in autism spectrum disorder (ASD). Topics explored are the prevalence of epilepsy in ASD, the importance of studying epilepsy, as well as the questionnaire measures used to assess epilepsy side-effects. Research on the relationships between epilepsy and parental stress and psychological distress, developmental regression, language and communication, adaptive behavior, social skills, autism severity, challenging behavior, comorbid psychopathology, gastrointestinal symptoms, sleep problems, sensory issues and quality of life are also discussed. Finally, recommendations for treatment are given as well as areas where future research is needed.     

The broad autism phenotype predicts child functioning in autism spectrum disorders

Background

Broad autism phenotype (BAP) is a milder expression of the social and communication impairments seen in autism spectrum disorders (ASD). While prior studies characterized the BAP in unaffected family members of probands with ASD, the relationship between parental BAP traits and proband symptomatology remains poorly understood. This study utilizes the Broad Autism Phenotype Questionnaire (BAPQ) in parents and the Social Responsiveness Scale (SRS) in children to examine this connection. We hypothesized that in families affected by ASD, elevated maternal and paternal BAPQ scores would correlate with greater autism symptomatology in diagnosed children. In an extension of prior research, we also explored this relationship in families with typically developing children (TDC).

Methods

Two hundred and forty-five children with ASD, 129 TDC and all parents were recruited as part of a larger study investigating relationships between genes, brain and behavior. The Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and expert clinical judgment confirmed ASD diagnoses in children. SRS was collected for all children. Parents completed a self-report BAPQ and an informant report BAPQ for their spouse; an average of self-report and informant report for each parent was used in all analyses.

Results

Mothers and fathers of children with ASD had significantly higher rates of BAP traits as compared to parents of TDC. Maternal and paternal BAPQ total scores were not correlated with child IQ in either group. In the ASD group, 10% of mothers and 21% of fathers scored above the established BAP threshold compared to 4% of TDC parents. Crude regression analyses showed that maternal and paternal BAPQ total scores accounted for significant variance in child SRS scores in both ASD (17.1%) and TDC (19.8%) families.

Conclusions

Our results suggest that broad autism symptomatology in parents is moderately associated with their child’s autism symptomatology. This result extended to TDC families, suggesting that the BAPQ and SRS capture subtle, subclinical social variation in both children and adults. These findings could help define multi-generational social impairments in future phenotypic and genetic studies.     

Variability in adaptive behaviour in young children with autism spectrum disorder

ABSTRACT

Background Understanding adaptive behaviour variability in children with autism spectrum disorder (ASD) may have important implications for early intervention. The purpose of this study was to explore whether autism symptom severity and caregiver depression affected adaptive behaviour in young children with ASD.

Method Data were collected from 60 primary caregivers of children aged 2–6 years with ASD. A factorial multivariate analysis of covariance was conducted to investigate if different levels of autism symptom severity and caregiver depression affected communication, socialisation, and daily living skills, after controlling for child age.

Results Findings suggest that only autism symptom severity accounted for significant variance in adaptive behaviour, with socialisation being most impacted. Although more than half of the caregivers reported heightened depressive symptoms, caregiver depression was not related to adaptive behaviour.

Conclusions Findings highlight the level of functional impairment that young children with ASD experience in relation to autism symptom severity.     

Copy‐number variation in the pathogenesis of autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy‐number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non‐allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy‐number dose‐dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.     

Network over‐connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other‐DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other‐DD including intellectual disability and language disorder) according to DSM‐IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (D_NUM) and the tract‐averaged fractional anisotropy (D_FA) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other‐DD groups. The network differences resulted in an over‐connectivity pattern (i.e., higher D_NUM and D_FA values) in the ASD group with a significance of P < 0.05. No contra‐comparison results were found. The over‐connectivity pattern in ASD occurred in networks primarily involving the fronto‐temporal nodes, known to be crucial for social‐skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network‐based diffusion study comparing toddlers with ASD and those with other‐DD. Results indicate the detection of different connectivity patterns in ASD and other‐DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333–2344, 2017. © 2017 Wiley Periodicals, Inc.     

Auditory attention in autism spectrum disorder: An exploration of volumetric magnetic resonance imaging findings

Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typically developing individuals on standardized measures of attention, even when controlling for IQ. The current study sought to examine within ASD whether anatomical correlates of attention performance differed between those with average to above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in comparison to typically developing controls (TDC). Using automated volumetric analyses, we examined regional volume of classic attention areas including the superior frontal gyrus, anterior cingulate cortex, and precuneus in ASD AIQ (n = 38) and LIQ (n = 18) individuals along with 30 TDC. Auditory attention performance was assessed using subtests of the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences in attention. The three groups did not differ significantly on any auditory attention-related brain volumes; however, trends toward significant size–attention function interactions were observed. Negative correlations were found between the volume of the precuneus and auditory attention performance for the AIQ ASD group, indicating larger volume related to poorer performance. Implications for general attention functioning and dysfunctional neural connectivity in ASD are discussed.     

Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study

Previous research has suggested an association between autism spectrum disorder (ASD) and allergic disorders, but epidemiological evidence regarding asthma remains limited. We conducted a nationwide population-based prospective cohort study (1:4 case:control patients, age- and gender-matched), hypothesizing that asthma in infancy or toddlerhood increased the risk of ASD. The participants comprised 2134 asthmatic infants and children and 8536 controls aged 0–3 years in 2002. We identified cases of ASD that occurred near the end of the follow-up period (December 31, 2010), determining that asthmatic infants and children exhibited a higher accumulative incidence rate of ASD than did the controls (1.3% vs 0.7%, P = .007). After adjusting for age at enrollment, gender, level of urbanization, and comorbid allergic diseases (i.e., allergic rhinitis and atopic dermatitis), asthmatic infants and children exhibited an elevated risk of developing ASD (hazard ratio: 2.01, 95% confidence interval: 1.19–3.40). This prospective study indicated a temporal relation between asthma and subsequent ASD diagnosis, supporting the immune hypothesis of ASD pathogenesis. Further studies are required to clarify the probable interactional effects between these disorders and define a homogenous ASD subgroup.     

The genetics of autism spectrum disorders

Epidemiological twin studies demonstrate that autism spectrum disorders (ASDs) represent genetic disorders. Subsequent analyses indicate that the causes of ASDs include less common single-gene mutations and chromosomal abnormalities, as well as ASDs caused by multiple interacting genes of weak effect. Genome-wide linkage analysis has identified several susceptibility loci for the ASDs, and positional and functional candidate genes have been identified that appear to represent susceptibility genes for the ASDs. Analysis of additional larger samples and the use of genome-wide association and high-throughput variant detection will lead to the identification of further genes for ASDs.     

Abnormal maturation of the resting‐state peak alpha frequency in children with autism spectrum disorder

Age‐related changes in resting‐state (RS) neural rhythms in typically developing children (TDC) but not children with autism spectrum disorder (ASD) suggest that RS measures may be of clinical use in ASD only for certain ages. The study examined this issue via assessing RS peak alpha frequency (PAF), a measure previous studies, have indicated as abnormal in ASD. RS magnetoencephalographic (MEG) data were obtained from 141 TDC (6.13–17.70 years) and 204 ASD (6.07–17.93 years). A source model with 15 regional sources projected the raw MEG surface data into brain source space. PAF was identified in each participant from the source showing the largest amplitude alpha activity (7‐13 Hz). Given sex differences in PAF in TDC (females > males) and relatively few females in both groups, group comparisons were conducted examining only male TDC (N = 121) and ASD (N = 183). Regressions showed significant group slope differences, with an age‐related increase in PAF in TDC (R² = 0.32) but not ASD (R² = 0.01). Analyses examining male children below or above 10‐years‐old (median split) indicated group effects only in the younger TDC (8.90 Hz) and ASD (9.84 Hz; Cohen's d = 1.05). In the older ASD, a higher nonverbal IQ was associated with a higher PAF. In the younger TDC, a faster speed of processing was associated with a higher PAF. PAF as a marker for ASD depends on age, with a RS alpha marker of more interest in younger versus older children with ASD. Associations between PAF and cognitive ability were also found to be age and group specific.     

Neural correlates of moral reasoning in autism spectrum disorder

In our study, we tried to clarify whether patients with autism spectrum disorder (ASD) reveal different moral decision patterns as compared to healthy subjects and whether common social interaction difficulties in ASD are reflected in altered brain activation during different aspects of moral reasoning. 28 patients with high-functioning ASD and 28 healthy subjects matched for gender, age and education took part in an event-related functional magnetic resonance imaging study. Participants were confronted with textual dilemma situations followed by proposed solutions to which they could agree or disagree. On a neural level, moral decision making was associated with activation in anterior medial prefrontal regions, the temporo-parietal junction and the precuneus for both groups. However, while patients and healthy controls did not exhibit significant behavioral differences, ASD patients showed decreased activation in limbic regions, particularly the amygdala, as well as increased activation in the anterior and the posterior cingulate gyrus during moral reasoning. Alterations of brain activation in patients might thus indicate specific impairments in empathy. However, activation increases in brain regions associated with the ‘default mode network’ and self-referential cognition also provide evidence for an altered way of patients’ cerebral processing with regard to decision making based on social information.     

A novel blood-based biomarker for detection of autism spectrum disorders

Autism spectrum disorders (ASD) are classified as neurological developmental disorders. Several studies have been carried out to find a candidate biomarker linked to the development of these disorders, but up to date no reliable biomarker is available. Mass spectrometry techniques have been used for protein profiling of blood plasma of children with such disorders in order to identify proteins/peptides that may be used as biomarkers for detection of the disorders. Three differentially expressed peptides with mass–charge (m/z) values of 2020±1, 1864±1 and 1978±1 Da in the heparin plasma of children with ASD that were significantly changed as compared with the peptide pattern of the non-ASD control group are reported here. This novel set of biomarkers allows for a reliable blood-based diagnostic tool that may be used in diagnosis and potentially, in prognosis of ASD.     

Emotion differentiation in autism spectrum disorder

Autism spectrum disorder (ASD) is commonly associated with reduced ability to recognize emotions in others. It is less clear however, whether ASD is also associated with impaired knowledge of one's own emotions. In the current study we present a first examination of how much knowledge individuals with ASD have about their emotions by investigating their ability to differentiate between emotions. Across two lab tasks that measured to what extent and how people differentiate between their own feeling states and semantic emotion terms, results showed that ASD individuals differentiated less than typically developing individuals. Yet, both groups of participants similarly categorized emotions according to previously established theoretical categories. These findings indicate that while both give similar meaning to emotions, individuals with ASD make less subtle distinctions between emotions. With low levels of emotion differentiation being linked to reduced well-being, these findings may help to better understand the high prevalence of internalizing problems associated with ASD.