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1.  Association study between autistic-like traits and polymorphisms in the autism candidate regions RELN, CNTNAP2, SHANK3, and CDH9/10 
Molecular Autism  2014;5(1):55.
Autistic-like traits (ALTs) are continuously distributed in the general population, with the autism spectrum disorder (ASD) at the upper extreme end. A genetic overlap has been shown between ALTs and ASD, indicating that common variation in ASD candidate genes may also influence ALTs. In our study, we have investigated the SNP rs4307059 that has been associated with both ALTs and ASD. In addition, we genotyped polymorphisms in a selection of genes involved in synaptic functioning, that is, SHANK3, RELN, and CNTNAP2, which repeatedly have been associated with ASD. The possible associations of these polymorphisms with ALTs, as well as genetic factors for neurodevelopmental problems (NDPs), were investigated in a large cohort from the general population: The Child and Adolescent Twin Study in Sweden. For analyses of ALTs and NDPs, 12,319 subjects (including 2,268 monozygotic (MZ) and 3,805 dizygotic (DZ) twin pairs) and 8,671 subjects (including 2,243 MZ and 2,044 DZ twin pairs), respectively, were included in the analyses.
We could not replicate the previous association between rs4307059 and social communication impairment. Moreover, common variations in CNTNAP2 (rs7794745 and rs2710102), RELN (rs362691), and SHANK3 (rs9616915) were not significantly associated with ALTs in our study.
Our results do not suggest that the investigated genes, which previously has been found associated with ASD diagnosis, have any major influence on ALTs in children from the general population.
Electronic supplementary material
The online version of this article (doi:10.1186/2040-2392-5-55) contains supplementary material, which is available to authorized users.
PMCID: PMC4276093  PMID: 25540679
Autistic-like traits; Autism spectrum disorder; CNTNAP2; RELN; rs4307059; SHANK3; A-TAC; CATSS
2.  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
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.  Common variation contributes to the genetic architecture of social communication traits 
Molecular Autism  2013;4:34.
Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype.
We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364).
Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009
Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027).
Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
PMCID: PMC3853437  PMID: 24047820
ALSPAC; RAINE; Autistic trait; GWAS; Social communication; Association
Journal of medical genetics  2013;51(1):10-20.
Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
PMCID: PMC4230531  PMID: 24101678
Psychiatric genetics  2014;24(6):241-248.
There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.
PMCID: PMC4320645  PMID: 25360606
association; autistic-like traits; MACROD2; Raine study; single nucleotide polymorphism
The American journal of psychiatry  2010;167(11):1349-1356.
Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings.
We report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register who met the criteria of having at least one child clinically-affected by an autism spectrum disorder (ASD) and at least one full biological sibling.
The occurrence of a traditionally-defined ASD in an additional child occurred in 10.9% of the families. An additional 20% of non-ASD-affected siblings had a history of language delay, half of whom had exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale (SRS) supported previously-reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families, and a relative absence of quantitative autistic traits among siblings in single-incidence autism families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts.
These data suggest that, depending on how it is defined, sibling recurrence in ASD may exceed previously-published estimates, and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism, and advance current understanding of the genetic epidemiology of autism.
PMCID: PMC2970737  PMID: 20889652
Genetics; Pervasive Developmental Disorder; Language; Broader Autism Phenotype
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
JAMA psychiatry  2014;71(8):936-942.
Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of sub-clinical autistic traits in non-clinical samples are poorly understood.
To determine the familiality of Social Responsiveness Scale (SRS) scores; we hypothesized that sub-clinical autistic traits would be associated in families.
Design and Setting
Nested case-control study within a population-based longitudinal cohort.
Participants were drawn from the Nurses’ Health Study II (NHS II), a cohort of 116,430 nurses. Cases were index children with reported ASD; controls were frequency matched by years of case births among those not reporting ASD. Of 3161 eligible participants, 2144 returned SRS forms for a child and at least one parent and were included in these analyses.
SRS scores, as reported by nurse participants/mothers and their spouses, were examined in association with liability to ASD using crude and adjusted logistic regression. Child SRS scores were examined in association with parental SRS scores using crude and adjusted linear regression, stratified by case status.
Main Outcome Measure
ASD, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised.
1,649 individuals were included in these analyses, representing 256 ASD cases, 1,393 controls, 1,233 mothers and 1,614 fathers. Index child SRS scores confirmed reported diagnoses. We report for the first time in a large epidemiologic sample that elevated parental quantitative autism traits (QAT) index risk for clinical ASD among offspring. The effect was most pronounced for fathers and for spousal pairs concordant for QAT elevation, which occurred more often than predicted by chance, due to significant preferential mating for QAT. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in approximately 20 points.
Conclusions and Relevance
These findings support the role of additive genetic influences in ASD, underscore the potential role of preferential mating in ASD population genetics, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.
PMCID: PMC4126195  PMID: 25100167
Biological Psychiatry  2014;76(8):664-671.
Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population.
Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥1) ADHD item (n = 3623).
Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥1 for ADHD traits, girls had a higher polygenic score than boys (p = .003).
These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.
PMCID: PMC4183378  PMID: 24673882
Attention-deficit/hyperactivity disorder; autism spectrum disorder; Avon Longitudinal Study of Parents and Children (ALSPAC); genetics; pragmatic language; social communication
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)
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
PMCID: PMC3866092  PMID: 24358029
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
To determine the association between Vitamin D and autism, and the difference in level of Vitamin D in autism children and control.
Case–control study conducted between June 2011 and May 2013, among autism at the Hamad Medical Corporation and controls at the School Health Clinics and Primary Health Care Clinics
Subjects and Methods:
A total of 254 cases and 254 controls. The Autism Diagnostic Observation Schedule-Generic is a semi-structured, standardized assessment of social interaction, communication, play and imaginative use of materials for individuals suspected of having autism spectrum disorders. Data on clinical manifestations and laboratory, family history, body mass index (BMI) and clinical biochemistry variables including serum 25-hydroxy Vitamin D, calcium, phosphorus and magnesium were obtained. Univariate and multivariate statistical analyzes were performed.
Of the total number of 508 children surveyed, 254 of autism and 254 of healthy children were contacted. The mean age (± standard deviation, in years) for autism versus control children was 5.51 ± 1.58 versus 5.76 ± 1.56. There were statistically significant differences between autism and healthy children control subjects with respect to educational level of mother (P = 0.016); occupation of mother (P = 0.005); BMI (P < 0.001); consanguinity (P = 0.015); exposure to sun (P = 0.002) and walking time per day <60 min (P < 0.001). The mean value of Vitamin D in autism children was much lower than the normal value, and there was a significant difference found in the mean values of Vitamin D between autism (18.39 ± 8.2 with median 18) and versus control children (21.59 ± 8.4) (P < 0.0001) and with median 21 (P = 0.004). Besides mean values of calcium, phosphorous, magnesium, glucose, potassium and alkaline phosphate were statistically significant higher in control healthy children compared to autism children (P < 0.001). Multivariate logistic regression analysis revealed that the mean serum Vitamin D level, calcium, consanguinity, BMI, physical activity, child order, and ferritin, were considered as the main factors associated with autism. Of total 254 of autism children, 14.2% had severe Vitamin D deficiency (<10 ng/ml), 43.7% had moderate insufficient levels (between 10 and 20 ng/ml), 28.3% had mild insufficient levels (between 20 and 30 ng/ml), and only 13.8% of autism had sufficient levels (>30 ng/ml). Similarly, of the total 254 of healthy children 8.3% had severe Vitamin D deficiency (<10 ng/ml), 37% had moderate insufficient levels (between 10 and 20 ng/ml), 37.4% had mild insufficient levels (between 20 and 30 ng/ml), and only 17.3% had sufficient levels (>30 ng/ml). Furthermore, there was statistically significant differences between autism and control subjects with respect to the serum level of Vitamin D (P = 0.023).
The present study revealed that Vitamin D deficiency was higher in autism children compared to healthy children and supplementing infants with Vitamin D might be a safe and more effective strategy for reducing the risk of autism.
PMCID: PMC4302541  PMID: 25624924
Association; autism; autism spectrum disorders; epidemiology; risk factors; Vitamin D
Neuroimage  2012;59(4-4):3356-3363.
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterised by impaired social interaction and communication, restricted interests and repetitive behaviours. The severity of these characteristics are posited to lie on a continuum extending into the typical population, and typical adults' performance on behavioural tasks that are impaired in ASD is correlated with the extent to which they display autistic traits (as measured by Autism Spectrum Quotient, AQ). Individuals with ASD also show structural and functional differences in brain regions involved in social perception. Here we show that variation in AQ in typically developing individuals is associated with altered brain activity in the neural circuit for social attention perception while viewing others' eye gaze. In an fMRI experiment, participants viewed faces looking at variable or constant directions. In control conditions, only the eye region was presented or the heads were shown with eyes closed but oriented at variable or constant directions. The response to faces with variable vs. constant eye gaze direction was associated with AQ scores in a number of regions (posterior superior temporal sulcus, intraparietal sulcus, temporoparietal junction, amygdala, and MT/V5) of the brain network for social attention perception. No such effect was observed for heads with eyes closed or when only the eyes were presented. The results demonstrate a relationship between neurophysiology and autism spectrum traits in the typical (non-ASD) population and suggest that changes in the functioning of the neural circuit for social attention perception is associated with an extended autism spectrum in the typical population.
► Autistic spectrum might extend to typically developing (TD) individuals. ► We studied TD individuals with varying Autism Spectrum Quotient (AQ). ► AQ correlated with BOLD response to viewing variable vs. constant eye gaze. ► AQ did not correlate with response to directional control stimuli. ► Neurophysiology and autism spectrum traits are associated in non-AS individuals.
PMCID: PMC3315678  PMID: 22062191
Eye gaze; fMRI; Autism spectrum; Attention; Face perception
Molecular Autism  2014;5:34.
There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
PMCID: PMC4228819  PMID: 25392729
BMC Neuroscience  2014;15(1):127.
Individuals with Williams syndrome, a neurogenetic condition caused by deletion of a set of genes at chromosomal location 7q11.23, exhibit a remarkable suite of traits including hypersociality with high, nonselective friendliness and low social anxiety, expressive language relatively well-developed but under-developed social-communication skills overall, and reduced visual-spatial abilities. Deletions and duplications of the Williams-syndrome region have also been associated with autism, and with schizophrenia, two disorders centrally involving social cognition. Several lines of evidence have linked the gene GTF2I (General Transcription Factor IIi) with the social phenotypes of Williams syndrome, but a role for this gene in sociality within healthy populations has yet to be investigated.
We genotyped a large set of healthy individuals for two single-nucleotide polymorphisms in the GTF2I gene that have recently been significantly associated with autism, and thus apparently exhibit functional effects on autism-related social phenotypes. GTF2I genotypes for these SNPs showed highly significant association with low social anxiety combined with reduced social-communication abilities, which represents a metric of the Williams-syndrome cognitive profile as described from previous studies.
These findings implicate the GTF2I gene in the neurogenetic basis of social communication and social anxiety, both in Williams syndrome and among individuals in healthy populations.
PMCID: PMC4247780  PMID: 25429715
Social behavior; Anxiety; Williams syndrome; Autism; GTF2I gene
In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.
We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.
We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).
Study limitations include our small sample size of postmortem brains.
Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.
PMCID: PMC4160358  PMID: 24866414
This study investigated the developmental course of autistic traits in a nationally-representative sample between ages 7 and 13.
The parents of 6,539 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, and 13. The phenotypic progression of autistic traits was assessed in the full sample and among high scoring individuals (e.g. top 10%, 5%). Gender, IQ, and overall behavior difficulties were examined as potentially relevant influences on autistic trait trajectories.
Autistic traits were highly stable in the general population, both overall and in high scoring groups. In the full sample, there was no change in mean SCDC scores for females between ages 7 and 13 (p=0.43). Male scores decreased slightly, but significantly, on the order of 0.1 standard deviations (p<0.001). There was no mean change in parent-rated autistic traits within any of the high scoring groups. IQ was not related to phenotypic progression; high parent-rated behavior problems predicted slight improvement in SCDC scores over the course of the study period among high scoring individuals (p<0.01).
These findings suggest that autistic traits are highly stable in the general population, even among individuals with the highest concentrations of autism-like behaviors. Phenotypic stability is consistent with expectations for individuals with ASD, providing further support for a phenomenological continuum across the clinical threshold. Moreover, the gap between female and male risk for autistic symptomology is consistent over time.
PMCID: PMC3174769  PMID: 21421177
Autism spectrum disorders; autistic traits; longitudinal analysis; ALSPAC
Molecular Autism  2010;1:8.
Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.
We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.
When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.
The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.
PMCID: PMC2913945  PMID: 20678250
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
Molecular Autism  2014;5(1):56.
There may be a link between anorexia nervosa and autism spectrum disorders. The aims of this study were to examine whether adolescents with anorexia nervosa have autism spectrum and/or obsessive-compulsive traits, how many would meet diagnostic criteria for autism spectrum disorder, and whether these traits are shared by parents.
A total of 150 adolescents receiving outpatient treatment for anorexia nervosa or subthreshold anorexia nervosa and their parents completed the autism spectrum disorder and eating disorder sections of the Development and Well-being Assessment. Patients also completed the Children Yale-Brown Obsessive-Compulsive Scale and other measures of psychiatric morbidity, and parents completed the short Autism Quotient and Obsessive-Compulsive Inventory Revised.
Adolescents with anorexia nervosa had a below average social aptitude (19% below cut-off) and high levels of peer relationship problems (39% above cut-off) and obsessive-compulsive symptoms (56% above cut-off). Six cases (4%, all females) were assigned a possible (n = 5) or definite (n = 1) diagnosis of autism spectrum disorder. Parental levels of autism spectrum and obsessive-compulsive traits were within the normal range.
This study suggests that adolescents with anorexia nervosa have elevated levels of autism spectrum traits, obsessive-compulsive symptoms, and a small proportion fulfil diagnostic criteria for a probable autism spectrum disorder. These traits did not appear to be familial. This comorbidity has been associated with a poorer prognosis. Therefore, adaptation of treatment for this subgroup may be warranted.
Trial registration ISRCTN83003225. Registered on 29 September 2011.
PMCID: PMC4280745  PMID: 25553237
Anorexia nervosa; Eating disorder; Autism spectrum disorder; Obsessive-compulsive disorder; Traits; Social aptitude; Adolescents; Parents; Development; Well-being assessment
Mædica  2011;6(4):247-257.
General information: Autism is a severe developmental disorder which involves social withdrawal, communication deficits, and stereotypic/repetitive behavior. The pathophysiological etiologies which precipitate autism symptoms remain elusive and controversial in many cases, but both genetic and environmental factors (and their interactions) have been implicated. While autism is considered multicausal, environmental factors have received significant attention. International discussion has ocused on neurotoxins such as mercury and lead, suggesting that these and other toxic metals contribute to the development of the disorder. An epidemiological study released in 2006 (Palmer et al.) linking Toxic Release Inventory (TRI) data on mercury to special education data in Texas reported a 61% increase in autism prevalence rates (or 17% adjusted) per 1000 pounds of mercury released into the environment (1). We attempted to further evaluate whether exposure to variable environmental contributes to the genesis of autistic spectrum disorder, and thus is a factor increasing the risk for developing autism symptoms in utero or in early childhood.
Purpose: The purpose of this study is to examine possible environmental risk factors and sources of exposure to mercury and other heavy metals in children with autism spectrum disorder versus controls. Through laboratory diagnostics we are able to distinguish between present and past exposure (i.e. hair analysis measurements reflect past exposure), urinary excretion levels of unprovoked urine represent immediate exposure. By assessing a spectrum of trace elements and heavy metals in hair and urine of both autistic and control groups, we focused on the participants≈ past and present exposure.
Methodology: The participants were 25 Autistic Spectrum Disorder (ASD) children (22 boys and 3 girls) between the age of 3 and 9 years. They were either diagnosed previously by other psychiatrist, psychologist, and developmental pediatrician or suspected by their parents as being autistic. All children were attendants to the Child Psychiatric Clinic in Erfan Psychiatric Hospital in Jeddah, KSA. Samples were collected during the period of June 2006 to March 2008. A control group of 25 children without any psychiatric or medical disorders was age-matched and sex-matched. All parents signed informed consent forms. All autistic children were subjected to a full clinical child psychiatric sheet for the diagnosis of autism spectrum disorder and exclusion of other psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) using the Arabic versions. Both groups were subjected to the Questionnaire on Exposure to Heavy Metals, Physical Symptoms, and Child Development. Hair and baseline urine samples (i.e. unprovoked urine) were taken from both groups and sent to the German clinical and environmental laboratory Micro Trace Minerals Gmbh, for the detection of heavy metals and trace elements levels where metal testing was performed via ICP-MS spectroscopy utilizing cell technique.
Results: By comparing the ASD Group to the Control Group, we found a statistically significant difference in the mean hair levels of arsenic, cadmium, barium, cerium and lead (p=0.01, 0.03, 0.003, 0.003, and 0.03 respectively), and in the mean hair levels of magnesium and zinc (p=0.001 and 0.003 respectively). There were also statistically significant differences in the mean urine levels of aluminum, barium, cerium, mercury, and lead (p=0.004, 002, 0.014, 0.006 and 0.004 respectively), and in the mean urine levels of copper and germanium (p=0.049 and 0.02 respectively). An agreement was found in both specimen (hair and urine) for barium and lead. The statistically significant differences in mean hair levels of arsenic, cadmium, and cerium were not supported by urine baseline levels. Also, the statistically significant magnesium and zinc levels of hair were not supported by urine levels. A disagreement was also found with copper and germanium concentrations.
PMCID: PMC3391939  PMID: 22879836
micronucleus; nucleoplasmic bridges; colon cancer
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
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

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