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1.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
PMCID: PMC2943511  PMID: 19404256
2.  Traits Contributing to the Autistic Spectrum 
PLoS ONE  2010;5(9):e12633.
It is increasingly recognised that traits associated with autism reflect a spectrum with no clear boundary between typical and atypical behaviour. Dimensional traits are needed to investigate the broader autism phenotype.
Methods and Principal Findings
Ninety-three individual measures reflecting components of social, communication and repetitive behaviours characterising autistic spectrum disorder (ASD) were identified between the ages of 6 months and 9 years from the ALSPAC database. Using missing value imputation, data for 13,138 children were analysed. Factor analysis suggested the existence of 7 factors explaining 85% of the variance. The factors were labelled: verbal ability, language acquisition, social understanding, semantic-pragmatic skills, repetitive-stereotyped behaviour, articulation and social inhibition. Four factors (1, 3, 5 and 7) were specific to ASD being more strongly associated with this phenotype than other co-morbid conditions while other factors were more associated with learning difficulties and specific language impairment. Nevertheless, all 7 factors contributed independently to the explanation of ASD (p<0.001). Exploration of putative genetic causal factors such as variants in the CNTNAP2 gene showed a varying pattern of associations with these traits. An alternative predictive model of ASD was derived using four individual measures: the coherence subscale of the Children's Communication Checklist (9y), the Social and Communication Disorders Checklist (91 m), repetitive behaviour (69 m) and the sociability subscale of the Emotionality Activity and Sociability measure (38 m). Although univarably these traits performed better than some factors, their combined explanations of ASD were similar (R2 = 0.48).
Conclusions and Significance
These results support the fractional nature of ASD with different aetiological origins for these components despite pleiotropic genetic effects being observed. These traits are likely to be useful in the exploration of ASD.
PMCID: PMC2935882  PMID: 20838614
3.  Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence 
Molecular Autism  2014;5:18.
Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).
GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007).
Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.
PMCID: PMC3940728  PMID: 24564958
ALSPAC; ASD; Autism; GCTA heritability; GWAS; Social communication
4.  The Broader Autism Phenotype and Its Implications on the Etiology and Treatment of Autism Spectrum Disorders 
Autism Research and Treatment  2011;2011:545901.
The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed the broader autism phenotype (BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD.
PMCID: PMC3420416  PMID: 22937250
5.  Default mode network in young male adults with autism spectrum disorder: relationship with autism spectrum traits 
Molecular Autism  2014;5:35.
Autism spectrum traits are postulated to lie on a continuum that extends between individuals with autism and individuals with typical development (TD). Social cognition properties that are deeply associated with autism spectrum traits have been linked to functional connectivity between regions within the brain’s default mode network (DMN). Previous studies have shown that the resting-state functional connectivities (rs-FCs) of DMN are low and show negative correlation with the level of autism spectrum traits in individuals with autism spectrum disorder (ASD). However, it is unclear whether individual differences of autism spectrum traits are associated with the strength of rs-FCs of DMN in participants including the general population.
Using the seed-based approach, we investigated the rs-FCs of DMN, particularly including the following two core regions of DMN: the anterior medial prefrontal cortex (aMPFC) and posterior cingulate cortex (PCC) in 19 young male adults with high-functioning ASD (mean age = 25.3 ± 6.9 years; autism-spectrum quotient (AQ) = 33.4 ± 4.2; full scale IQ (F-IQ) = 109.7 ± 12.4) compared with 21 age- and IQ-matched young male adults from the TD group (mean age = 24.8 ± 4.3 years; AQ = 18.6 ± 5.7; F-IQ = 109.5 ± 8.7). We also analyzed the correlation between the strength of rs-FCs and autism spectrum traits measured using AQ score.
The strengths of rs-FCs from core regions of DMN were significantly lower in ASD participants than TD participants. Under multiple regression analysis, the strengths of rs-FCs in brain areas from aMPFC seed showed negative correlation with AQ scores in ASD participants and TD participants.
Our findings suggest that the strength of rs-FCs in DMN is associated with autism spectrum traits in the TD population as well as patients with ASD, supporting the continuum view. The rs-FCs of DMN may be useful biomarkers for the objective identification of autism spectrum traits, regardless of ASD diagnosis.
PMCID: PMC4064274  PMID: 24955232
Autism spectrum disorder (ASD); Autism spectrum traits; Autism-spectrum quotient (AQ); Default mode network (DMN); Resting-state functional connectivities (rs-FCs); Anterior medial prefrontal cortex (aMPFC); Posterior cingulate cortex (PCC)
6.  Autism Spectrum Traits in the Typical Population Predict Structure and Function in the Posterior Superior Temporal Sulcus 
Cerebral Cortex (New York, NY)  2010;21(3):493-500.
Autism spectrum disorders (ASDs) are typically characterized by impaired social interaction and communication, narrow interests, and repetitive behaviors. The heterogeneity in the severity of these characteristics across individuals with ASD has led some researchers to suggest that these disorders form a continuum which extends into the general, or “typical,” population, and there is growing evidence that the extent to which typical adults display autistic traits, as measured using the autism-spectrum quotient (AQ), predicts performance on behavioral tasks that are impaired in ASD. Here, we show that variation in autism spectrum traits is related to cortical structure and function within the typical population. Voxel-based morphometry showed that increased AQ scores were associated with decreased white matter volume in the posterior superior temporal sulcus (pSTS), a region important in processing socially relevant stimuli and associated with structural and functional impairments in ASD. In addition, AQ was correlated with the extent of cortical deactivation of an adjacent area of pSTS during a Stroop task relative to rest, reflecting variation in resting state function. The results provide evidence that autism spectrum characteristics are reflected in neural structure and function across the typical (non-ASD) population.
PMCID: PMC3041005  PMID: 20439317
autism; fMRI; resting state; voxel-based morphometry
7.  Brief Report: IQ Split Predicts Social Symptoms and Communication Abilities in High-Functioning Children with Autism Spectrum Disorders 
We investigated the relationship of discrepancies between VIQ and NVIQ (IQ split) to autism symptoms and adaptive behavior in a sample of high-functioning (mean FSIQ = 98.5) school-age children with autism spectrum disorders divided into three groups: discrepantly high VIQ (n = 18); discrepantly high NVIQ (n = 24); and equivalent VIQ and NVIQ (n = 36). Discrepantly high VIQ and NVIQ were associated with autism social symptoms but not communication symptoms or repetitive behaviors. Higher VIQ and NVIQ were associated with better adaptive communication but not socialization or Daily Living Skills. IQ discrepancy may be an important phenotypic marker in autism. Although better verbal abilities are associated with better functional outcomes in autism, discrepantly high VIQ in high-functioning children may also be associated with social difficulties.
PMCID: PMC3042799  PMID: 19572193
Autism; Cognitive profiles; IQ; Symptomatology; Adaptive functioning; Asperger syndrome
8.  Novel Autism Subtype-Dependent Genetic Variants Are Revealed by Quantitative Trait and Subphenotype Association Analyses of Published GWAS Data 
PLoS ONE  2011;6(4):e19067.
The heterogeneity of symptoms associated with autism spectrum disorders (ASDs) has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL), were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression) than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders.
PMCID: PMC3083416  PMID: 21556359
9.  Can Family Affectedness Inform Infant Sibling Outcomes of Autism Spectrum Disorders? 
Difficulties in communication and reciprocal social behavior are core features of autism spectrum disorders (ASD) and are often present, to varying degrees, in other family members. This prospective longitudinal infant sibling study examines whether social-communicative features of family members may inform which infants are at increased risk for ASD and other developmental concerns.
Two hundred and seventeen families participated in this study. Infant siblings were recruited from families with at least one older child diagnosed with an ASD (n = 135) or at least one typically developing older child (n = 82). Families completed the Social Responsiveness Scale to assess social and communication features of the broader autism phenotype (BAP), sometimes called quantitative autistic traits (QAT). Family affectedness was assessed in two ways: categorically, based on number of affected older siblings (i.e., typical, simplex, multiplex risk groups) and dimensionally, by assessing varying degrees of QAT in all family members. Infant siblings were assessed at 36 months of age and completed the Autism Diagnostic Observation Schedule and the Mullen Scales of Early Learning.
In structural equation models, comparisons between multiplex, simplex and typical groups revealed the highest rates of QAT in the multiplex group followed by the simplex and typical groups. Infant sibling outcomes were predicted by gender, family risk group, proband QAT, and additional sibling QAT.
Replicating previous cross-sectional and family history findings, the present study found elevated social and communication features of the BAP in siblings and fathers of ASD families, but not in mothers. While social and communication features of the BAP in mothers, fathers, and undiagnosed siblings did not predict infant sibling outcomes, having more than one affected older sibling did. Infant siblings from multiplex families were at significantly higher risk for ASD than infant siblings from simplex families in this sample.
PMCID: PMC2922056  PMID: 20546079
Autistic disorder; Pervasive developmental disorder; family factors; siblings; structural equation modeling
10.  The Dyslexia Candidate Locus on 2p12 Is Associated with General Cognitive Ability and White Matter Structure 
PLoS ONE  2012;7(11):e50321.
Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
PMCID: PMC3509064  PMID: 23209710
11.  Gender Differences in the Relationship Between Social Communication and Emotion Recognition 
To investigate the association between autistic traits and emotion recognition in a large community sample of children using facial and social motion cues, additionally stratifying by gender.
A general population sample of 3,666 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed on their ability to correctly recognize emotions using the faces subtest of the Diagnostic Analysis of Non-Verbal Accuracy, and the Emotional Triangles Task, a novel test assessing recognition of emotion from social motion cues. Children with autistic-like social communication difficulties, as assessed by the Social Communication Disorders Checklist, were compared with children without such difficulties.
Autistic-like social communication difficulties were associated with poorer recognition of emotion from social motion cues in both genders, but were associated with poorer facial emotion recognition in boys only (odds ratio = 1.9, 95% CI = 1.4, 2.6, p = .0001). This finding must be considered in light of lower power to detect differences in girls.
In this community sample of children, greater deficits in social communication skills are associated with poorer discrimination of emotions, implying there may be an underlying continuum of liability to the association between these characteristics. As a similar degree of association was observed in both genders on a novel test of social motion cues, the relatively good performance of girls on the more familiar task of facial emotion discrimination may be due to compensatory mechanisms. Our study might indicate the existence of a cognitive process by which girls with underlying autistic traits can compensate for their covert deficits in emotion recognition, although this would require further investigation.
PMCID: PMC3989041  PMID: 24157389
autism spectrum disorder (ASD); Avon Longitudinal Study of Parents and Children (ALSPAC); emotion recognition; gender; social communication
12.  Spontaneous Belief Attribution in Younger Siblings of Children on the Autism Spectrum 
Developmental Psychology  2013;50(3):903-913.
The recent development in the measurements of spontaneous mental state understanding, employing eye-movements instead of verbal responses, has opened new opportunities for understanding the developmental origin of “mind-reading” impairments frequently described in autism spectrum disorders (ASDs). Our main aim was to characterize the relationship between mental state understanding and the broader autism phenotype, early in childhood. An eye-tracker was used to capture anticipatory looking as a measure of false beliefs attribution in 3-year-old children with a family history of autism (at-risk participants, n = 47) and controls (control participants, n = 39). Unlike controls, the at-risk group, independent of their clinical outcome (ASD, broader autism phenotype or typically developing), performed at chance. Performance was not related to children’s verbal or general IQ, nor was it explained by children “missing out” on crucial information, as shown by an analysis of visual scanning during the task. We conclude that difficulties with using mental state understanding for action prediction may be an endophenotype of autism spectrum disorders.
PMCID: PMC3942014  PMID: 23978296
autism; family risk; false belief; eye-tracking
13.  Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism 
Molecular Autism  2013;4:48.
Autism spectrum conditions (ASC) are associated with deficits in social interaction and communication, alongside repetitive, restricted, and stereotyped behavior. ASC is highly heritable. The gamma-aminobutyric acid (GABA)-ergic system has been associated consistently with atypicalities in autism, in both genetic association and expression studies. A key component of the GABA-ergic system is encoded by the GABRB3 gene, which has been previously implicated both in ASC and in individual differences in empathy.
In this study, 45 genotyped single nucleotide polymorphisms (SNPs) within GABRB3 were tested for association with Asperger syndrome (AS), and related quantitative traits measured through the following tests: the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ), the Systemizing Quotient-Revised (SQ-R), the Embedded Figures Test (EFT), the Reading the Mind in the Eyes Test (RMET), and the Mental Rotation Test (MRT). Two-loci, three-loci, four-loci haplotype analyses, and one seven-loci haplotype analysis were also performed in the AS case–control sample.
Three SNPs (rs7180158, rs7165604, rs12593579) were significantly associated with AS, and two SNPs (rs9806546, rs11636966) were significantly associated with EQ. Two SNP-SNP pairs, rs12438141-rs1035751 and rs12438141-rs7179514, showed significant association with variation in the EFT scores. One SNP-SNP pair, rs7174437-rs1863455, was significantly associated with variation in the MRT scores. Additionally, a few haplotypes, including a 19 kb genomic region that formed a linkage disequilibrium (LD) block in our sample and contained several nominally significant SNPs, were found to be significantly associated with AS.
The current study confirms the role of GABRB3 as an important candidate gene in both ASC and normative variation in related endophenotypes.
PMCID: PMC3903107  PMID: 24321478
Asperger syndrome; Autism spectrum conditions; Empathy; Embedded Figures Test; Mental Rotation Test; GABA receptor
14.  The Quantitative Nature of Autistic Social Impairment 
Pediatric research  2011;69(5 Pt 2):55R-62R.
Autism, like intellectual disability, represents the severe end of a continuous distribution of developmental impairments that occur in nature, that are highly inherited, and that are orthogonally related to other parameters of development. A paradigm shift in understanding the core social abnormality of autism as a quantitative trait rather than as a categorically-defined condition has key implications for diagnostic classification, the measurement of change over time, the search for underlying genetic and neurobiologic mechanisms, and public health efforts to identify and support affected children. Here a recent body of research in genetics and epidemiology is presented to examine a dimensional reconceptualization of autistic social impairment—as manifested in clinical autistic syndromes, the broader autism phenotype, and normal variation in the general population. It illustrates how traditional categorical approaches to diagnosis may lead to misclassification of subjects (especially girls and mildly affected boys in multiple-incidence autism families), which can be particularly damaging to biological studies, and proposes continued efforts to derive a standardized quantitative system by which to characterize this family of conditions.
PMCID: PMC3086844  PMID: 21289537
15.  Brief Report: No Association Between Parental Age and Extreme Social-Communicative Autistic Traits in the General Population 
This is the first investigation of the relationship between parental age and extreme social-communicative autistic traits in the general population. The parents of 5,246 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC). The association between parental age and SCDC scores was assessed in the full sample and among high scoring individuals (e.g. top 5%, 1%). There was no association between parental age and social-communicative autistic traits in the general population. Neither maternal nor paternal age was associated with extreme scores. These findings suggest that advanced parental age does not confer increased risk for extreme social and communication impairment assessed quantitatively.
PMCID: PMC3160499  PMID: 21350918
Autism spectrum disorders; Autistic traits; arental age; ALSPAC
16.  Are Autistic Traits in the General Population Stable across Development? 
PLoS ONE  2011;6(8):e23029.
There is accumulating evidence that autistic traits (AT) are on a continuum in the general population, with clinical autism representing the extreme end of a quantitative distribution. While the nature and severity of symptoms in clinical autism are known to persist over time, no study has examined the long-term stability of AT among typically developing toddlers. The current investigation measured AT in 360 males and 400 males from the general population close to two decades apart, using the Pervasive Developmental Disorder subscale of the Child Behavior Checklist in early childhood (M = 2.14 years; SD = 0.15), and the Autism-Spectrum Quotient in early adulthood (M = 19.50 years; SD = 0.70). Items from each scale were further divided into social (difficulties with social interaction and communication) and non-social (restricted and repetitive behaviours and interests) AT. The association between child and adult measurements of AT as well the influence of potentially confounding sociodemographic, antenatal and obstetric variables were assessed using Pearson's correlations and linear regression. For males, Total AT in early childhood were positively correlated with total AT (r = .16, p = .002) and social AT (r = .16, p = .002) in adulthood. There was also a positive correlation for males between social AT measured in early childhood and Total (r = .17, p = .001) and social AT (r = .16, p = .002) measured in adulthood. Correlations for non-social AT did not achieve significance in males. Furthermore, there was no significant longitudinal association in AT observed for males or females. Despite the constraints of using different measures and different raters at the two ages, this study found modest developmental stability of social AT from early childhood to adulthood in boys.
PMCID: PMC3150391  PMID: 21829684
17.  Validation of Autism Spectrum Quotient Adult Version in an Australian Sample 
Autism Research and Treatment  2013;2013:984205.
The Autism Spectrum Quotient is used to assess autistic spectrum traits in intellectually competent adults in both the general population and the autism spectrum community. While the autism spectrum Quotient has been validated in several different cultures, to date no study has assessed the psychometrics of the Autism Spectrum Quotient on an Australian population. The purpose of this study was to assess the psychometrics of the autism spectrum Quotient in an Australian sample of both typically developing individuals (n = 128) and individuals with autism spectrum disorder (n = 104). The results revealed that the internal consistency and the test-retest reliability were satisfactory; individuals with autism spectrum disorder scored higher on total Autism Spectrum Quotient score and its subscales than typically developing individuals; however, gender differences were not apparent on total score. Possible cultural differences may explain some of the psychometric variations found. The results of this analysis revealed that the Autism Spectrum Quotient was a reliable instrument for investigating variation in autistic symptomology in both typically developing and Autism Spectrum Disorders populations within an Australian population.
PMCID: PMC3665170  PMID: 23762552
18.  The broad autism phenotype predicts child functioning in autism spectrum disorders 
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).
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.
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.
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.
PMCID: PMC3848833  PMID: 24053506
Autism spectrum disorders; Broad autism phenotype; Social functioning
19.  Autistic trait interactions underlie sex-dependent facial recognition abilities in the normal population 
Autistic face processing difficulties are either uniquely social or due to a piecemeal cognitive “style.” Co-morbidity of social deficits and piecemeal cognition in autism makes teasing apart these accounts difficult. These traits vary normally, and are more separable in the general population, suggesting another way to compare accounts. Participants completed the Autism Quotient survey of autistic traits, and one of three face recognition tests: full-face, eyes-only, or mouth-only. Social traits predicted performance in the full-face condition in both sexes. Eyes-only males' performance was predicted by a social × cognitive trait interaction: attention to detail boosted face recognition in males with few social traits, but hindered performance in those reporting many social traits. This suggests social/non-social Autism Spectrum Conditions (ASC) trait interactions at the behavioral level. In the presence of few ASC-like difficulties in social reciprocity, an ASC-like attention to detail may confer advantages on typical males' face recognition skills. On the other hand, when attention to detail co-occurs with difficulties in social reciprocity, a detailed focus may exacerbate such already present social difficulties, as is thought to occur in autism.
PMCID: PMC3668264  PMID: 23755028
autism; cognitive variation; sex differences; face recognition; face processing
20.  Developing a Predictive Gene Classifier for Autism Spectrum Disorders Based upon Differential Gene Expression Profiles of Phenotypic Subgroups 
North American journal of medicine & science  2013;6(3):10.7156/najms.2013.0603107.
Autism spectrum disorders (ASD) are neurodevelopmental disorders which are currently diagnosed solely on the basis of abnormal stereotyped behavior as well as observable deficits in communication and social functioning. Although a variety of candidate genes have been identified on the basis of genetic analyses and up to 20% of ASD cases can be collectively associated with a genetic abnormality, no single gene or genetic variant is applicable to more than 1–2 percent of the general ASD population. In this report, we apply class prediction algorithms to gene expression profiles of lymphoblastoid cell lines (LCL) from several phenotypic subgroups of idiopathic autism defined by cluster analyses of behavioral severity scores on the Autism Diagnostic Interview-Revised diagnostic instrument for ASD. We further demonstrate that individuals from these ASD subgroups can be distinguished from nonautistic controls on the basis of limited sets of differentially expressed genes with a predicted classification accuracy of up to 94% and sensitivities and specificities of ~90% or better, based on support vector machine analyses with leave-one-out validation. Validation of a subset of the “classifier” genes by high-throughput quantitative nuclease protection assays with a new set of LCL samples derived from individuals in one of the phenotypic subgroups and from a new set of controls resulted in an overall class prediction accuracy of ~82%, with ~90% sensitivity and 75% specificity. Although additional validation with a larger cohort is needed, and effective clinical translation must include confirmation of the differentially expressed genes in primary cells from cases earlier in development, we suggest that such panels of genes, based on expression analyses of phenotypically more homogeneous subgroups of individuals with ASD, may be useful biomarkers for diagnosis of subtypes of idiopathic autism.
PMCID: PMC3867975  PMID: 24363828
Autism; subphenotypes; gene expression; class prediction; blood biomarkers
21.  Factor Structure of Autistic Traits in Children with ADHD 
Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur. Factor analyses of ASD traits in children with and without ASD indicate the presence of social and restrictive–repetitive behaviour (RRB) factors. This study used exploratory factor analyses to determine the structure of ASD traits (assessed using the Social Communication Questionnaire) in children with ADHD. Distinct factors were observed for ‘social’ and ‘rigidity’ traits, corresponding to previous factor analyses in clinical ASD and population samples. This indicates that the split between social-communicative and RRB dimensions is unaffected by ADHD in children. Moreover, the study also finds that there is some overlap across hyperactive-impulsive symptoms and RRB traits in children with ADHD, which merits further investigation.
PMCID: PMC3898364  PMID: 23748436
ADHD; ASD; Factor analysis; Neurodevelopment
22.  Facial Identity Recognition in the Broader Autism Phenotype 
PLoS ONE  2010;5(9):e12876.
The ‘broader autism phenotype’ (BAP) refers to the mild expression of autistic-like traits in the relatives of individuals with autism spectrum disorder (ASD). Establishing the presence of ASD traits provides insight into which traits are heritable in ASD. Here, the ability to recognise facial identity was tested in 33 parents of ASD children.
Methodology and Results
In experiment 1, parents of ASD children completed the Cambridge Face Memory Test (CFMT), and a questionnaire assessing the presence of autistic personality traits. The parents, particularly the fathers, were impaired on the CFMT, but there were no associations between face recognition ability and autistic personality traits. In experiment 2, parents and probands completed equivalent versions of a simple test of face matching. On this task, the parents were not impaired relative to typically developing controls, however the proband group was impaired. Crucially, the mothers' face matching scores correlated with the probands', even when performance on an equivalent test of matching non-face stimuli was controlled for.
Conclusions and Significance
Components of face recognition ability are impaired in some relatives of ASD individuals. Results suggest that face recognition skills are heritable in ASD, and genetic and environmental factors accounting for the pattern of heritability are discussed. In general, results demonstrate the importance of assessing the skill level in the proband when investigating particular characteristics of the BAP.
PMCID: PMC2943915  PMID: 20877561
23.  Predictive value of subclinical autistic traits at age 14–15 months for behavioural and cognitive problems at age 3–5 years 
It is unclear whether subclinical autistic traits at very young age are transient or stable, and have clinical relevance. This study investigated the relationship between early subclinical autistic traits and the occurrence of later developmental and behavioural problems as well as problems in cognitive and language functioning. Parents of infants aged 14–15 months from the general population completed the Early Screening of Autistic Traits Questionnaire (ESAT). Three groups of children with high, moderate, and low ESAT-scores (total n = 103) were selected. Follow-up assessments included the CBCL 1½–5 at age 3 years, and the SCQ, the ADI-R, the ADOS-G, a non-verbal intelligence test, and language tests for comprehension and production at age 4–5 years. None of the children met criteria for autism spectrum disorder at follow-up. Children with high ESAT-scores at 14–15 months showed significantly more internalizing and externalizing problems at age 3 years and scored significantly lower on language tests at age 4–5 years than children with moderate or low ESAT-scores. Further, significantly more children with high ESAT-scores (14/26, 53.8%) than with moderate and low ESAT-scores (5/36, 13.9% and 1/41, 2.4%, respectively) were in the high-risk/clinical range on one or more outcome domains (autistic symptoms, behavioural problems, cognitive and language abilities). Subclinical autistic traits at 14–15 months predict later behavioural problems and delays in cognitive and language functioning rather than later ASD-diagnoses. The theoretical implications of the findings lie in the pivotal role of early social and communication skills for the development of self-regulation of emotions and impulses. The practical implications bear on the early recognition of children at risk for behavioural problems and for language and cognitive problems.
PMCID: PMC2910304  PMID: 20390313
Autistic traits; Behavioural problems; Cognitive abilities; Young children; General population
24.  Translational animal models of autism and neurodevelopmental disorders 
Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.
PMCID: PMC3513683  PMID: 23226954
neurodevelopmental disorder; autism; genetics; mouse model; social behavior; therapeutics; olfactory; ultrasonic vocalization; repetitive behavior; self-grooming; anxiety; cognitive; Fragile X; tuberous sclerosis; mGluRS antagonist
25.  Autistic Traits and Brain Activation during Face-to-Face Conversations in Typically Developed Adults 
PLoS ONE  2011;6(5):e20021.
Autism spectrum disorders (ASD) are characterized by impaired social interaction and communication, restricted interests, and repetitive behaviours. The severity of these characteristics is posited to lie on a continuum that extends into the general population. Brain substrates underlying ASD have been investigated through functional neuroimaging studies using functional magnetic resonance imaging (fMRI). However, fMRI has methodological constraints for studying brain mechanisms during social interactions (for example, noise, lying on a gantry during the procedure, etc.). In this study, we investigated whether variations in autism spectrum traits are associated with changes in patterns of brain activation in typically developed adults. We used near-infrared spectroscopy (NIRS), a recently developed functional neuroimaging technique that uses near-infrared light, to monitor brain activation in a natural setting that is suitable for studying brain functions during social interactions.
We monitored regional cerebral blood volume changes using a 52-channel NIRS apparatus over the prefrontal cortex (PFC) and superior temporal sulcus (STS), 2 areas implicated in social cognition and the pathology of ASD, in 28 typically developed participants (14 male and 14 female) during face-to-face conversations. This task was designed to resemble a realistic social situation. We examined the correlations of these changes with autistic traits assessed using the Autism-Spectrum Quotient (AQ).
Principal Findings
Both the PFC and STS were significantly activated during face-to-face conversations. AQ scores were negatively correlated with regional cerebral blood volume increases in the left STS during face-to-face conversations, especially in males.
Our results demonstrate successful monitoring of brain function during realistic social interactions by NIRS as well as lesser brain activation in the left STS during face-to-face conversations in typically developed participants with higher levels of autistic traits.
PMCID: PMC3103507  PMID: 21637754

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