Dataset Information

Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.

ABSTRACT: Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple sub-threshold social, communicative, and cognitive impairments.Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.

SUBMITTER: St Pourcain B

PROVIDER: S-EPMC3008767 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.

St Pourcain Beate B Wang Kai K Glessner Joseph T JT Golding Jean J Steer Colin C Ring Susan M SM Skuse David H DH Grant Struan F A SF Hakonarson Hakon H Davey Smith George G

The American journal of psychiatry 20100715 11

<h4>Objective</h4>Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.<h4>Method</h4>Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single ...[more]

PMID: 20634369

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Project description:BACKGROUND:More refined dimensions of social-communication impairment are needed to elucidate the clinical and biological boundaries of autism spectrum disorders (ASD) and other childhood onset psychiatric disorders associated with social difficulties, as well as to facilitate investigations in treatment and long-term outcomes of these disorders. METHODS:This study was intended to identify separable dimensions of clinician-observed social-communication impairments by examining scores on a widely used autism diagnostic instrument. Participants included verbally fluent children ages 3-13 years, who were given a clinical diagnosis of ASD (n = 120) or non-ASD (i.e. ADHD, language disorder, intellectual disability, mood or anxiety disorder; n = 118) following a comprehensive diagnostic assessment. Exploratory and confirmatory factor analysis examined the factor structure of algorithm items from the Autism Diagnostic Observation Schedule (ADOS), Module 3. RESULTS:Results indicated that a three-factor model consisting of repetitive behaviors and two separate social-communication behavior factors had superior fit compared to a two-factor model that included repetitive behaviors and one social-communication behavior factor. In the three-factor model, impairments in 'Basic Social-Communication' behaviors (e.g. eye contact, facial expressions, gestures) were separated from impairments in 'Interaction quality.' Confirmatory factor analysis in an independent sample of children in the Simons Simplex Collection (SSC) further supported the division of social-communication impairments into these two factors. Scores in Interaction Quality were significantly associated with nonverbal IQ and male sex in the ASD group, and with age in the non-ASD group, while scores in basic social communication were not significantly associated with any of these child characteristics in either diagnostic group. CONCLUSIONS:Efforts to conceptualize level, or severity, of social-communication impairment in children with neurodevelopmental disorders might be facilitated by separating the most basic (or proximal) social-communication impairments from those that could arise from a range of other phenotypic variables. Identification of social-communication subdimensions also highlights potential avenues for measuring different types of social-communication impairments for different purposes (e.g. for differential diagnosis vs. response to treatment).

Project description:Neuroimaging studies of individuals with autism spectrum disorders (ASDs) consistently find an aberrant pattern of reduced laterality in brain networks that support functions related to social communication and language. However, it is unclear how the underlying functional organization of these brain networks is altered in ASD individuals. We tested four models of reduced laterality in a social communication network in 70 ASD individuals (14 females) and a control group of the same number of tightly matched typically developing (TD) individuals (19 females) using high-quality resting-state fMRI data and a method of measuring patterns of functional laterality across the brain. We found that a functionally defined social communication network exhibited the typical pattern of left laterality in both groups, whereas there was a significant increase in within- relative to across-hemisphere connectivity of homotopic regions in the right hemisphere in ASD individuals. Furthermore, greater within- relative to across-hemisphere connectivity in the left hemisphere was positively correlated with a measure of verbal ability in both groups, whereas greater within- relative to across-hemisphere connectivity in the right hemisphere in ASD, but not TD, individuals was negatively correlated with the same verbal measure. Crucially, these differences in patterns of laterality were not found in two other functional networks and were specifically correlated to a measure of verbal ability but not metrics of other core components of the ASD phenotype. These results suggest that previous reports of reduced laterality in social communication regions in ASD is because of the two hemispheres functioning more independently than seen in TD individuals, with the atypical right-hemisphere network component being maladaptive.SIGNIFICANCE STATEMENT A consistent neuroimaging finding in individuals with ASD is an aberrant pattern of reduced laterality of the brain networks that support functions related to social communication and language. We tested four models of reduced laterality in a social communication network in ASD individuals and a TD control group using high-quality resting-state fMRI data. Our results suggest that reduced laterality of social communication regions in ASD may be because of the two hemispheres functioning more independently than seen in TD individuals, with atypically greater within- than across-hemisphere connectivity in the right hemisphere being maladaptive.

Project description:BackgroundRecognition of symptoms of Social anxiety (SA) may be difficult among individuals with Autism Spectrum Disorders (ASD) because of overlap between social anxiety and autistic symptomatology. The main aim of our study was thus to explore the association between symptoms of social anxiety and clinical characteristics of ASD in order to identify individuals experiencing concomitant ASD and social anxiety disorder. We also described the prevalence of SA in a sample of children and adolescents with ASD.Method79 children and adolescents with ASD (with and without intellectual disability) and 28-matched control participants were recruited in two French Expert Centers for ASD, coordinated by the Fundation FondaMental. Psychiatric comorbidities, anxiety disorders and depression were screened with standard tools (Liebowitz social anxiety scale, Hamilton Depression and Anxiety Rating Scale) and correlated to autistic features and social skills assessed with the social responsiveness scale 2 (SRS-2) and the repetitive behavior scale (RBS-R). We performed bivariate analysis between the social anxiety level and the scores measured with different clinical scales. We then adjusted the observed relationships with the alterations of SRS-2 and RBS-R scores.ResultsAfter adjustment, the level of social anxiety appeared as significantly associated with alterations in social reciprocity and particularly with the SRS-2 "social communication" and "social motivation" sub-scores, but not with RBS-R score.ConclusionsWe confirm previous reports showing that individuals with ASD are at high risk for specific anxiety disorders. In particular, high levels of impairments in social motivation and social communication (SRS-2) are indicative of comorbid disorders namely, social anxiety and ASD. Our findings clearly inform diagnostic assessment in ASD and stress the need to take comorbid anxiety disorders into consideration to improve treatment of ASD. To further clarify the impact of social anxiety on social competences and socio-adaptive handicap, longitudinal studies and cluster analysis will be needed in the future.

Project description:ImportanceThere are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties.ObjectiveTo evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD.Design, setting, and participantsThe aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020.InterventionsParticipants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued.Main outcomes and measuresThe primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24.ResultsBetween November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]).Conclusions and relevanceIn this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD.Trial registrationClinicalTrials.gov Identifier: NCT02901431.

Project description:Background & aimsSocial communication and language skills have been found to be important predictors of long-term outcomes in individuals with autism spectrum disorder (ASD). However, the development of coordinated social communication (i.e., gestures and sounds or words) remains relatively understudied in young children with ASD and developmental delays (DD). This study used a prospective, longitudinal design and granular observational coding to document the coordination of gestures, sounds, and words in a large, heterogeneous sample of toddlers identified with ASD, DD, or typical development (TD) during a naturalistic home observation. Specific aims were: (1) to compare rates per minute and proportions of coordinated child communicative acts across groups; (2) to examine concurrent relationships between coordinated communication and measures of social communication and autism symptoms; and (3) to examine prospective relationships between coordinated communication, receptive and expressive language skills, and autism symptoms collected at 3 years of age.MethodsAt a mean age of 20.3 months (SD = 2.0), 211 children (nASD = 121; nDD = 46; nTD = 44) participated in everyday activities with a parent during an hourlong home observation. Rates per minute and proportions of gestures, sounds and words, as well as temporally overlapping gesture + sound, gesture + word, and gesture + phrase combinations, were compared using one-way ANOVA. Pearson product moment correlations between coordinated communicative acts and measures of social communication, language, and autism symptoms were examined.ResultsOn average, children with ASD used sounds and gesture + sounds at significantly lower rates than DD and TD groups, who did not differ. Children with ASD and DD coordinated gesture + single words and gesture + phrases at significantly lower rates than the TD group. Groups did not differ with respect to the rate per minute at which they used gestures alone. Children with TD used a smaller proportion of sounds alone and higher proportions of words and phrases, with and without coordinated gestures, than ASD and DD groups. Children with ASD and DD used a significantly higher proportion of gestures alone than children with TD. Rates per minute and proportions of single words and gesture + words had significant correlations with measures of social communication, language skills, and autism symptoms.ConclusionsResults suggest that a significantly lower rate per minute of sounds and gesture + sound combinations was a distinguishing feature of ASD in our sample. Further, limited use of single words and gesture + single words was observed in children ASD and DD. Significant prospective relationships between single words and gesture + words with language skills measured over a year later underscores the importance of acquiring these forms.ImplicationsResults support the idea that clinicians should include opportunities to observe and encourage coordinated social communication while screening and assessing young children for DD and ASD in the home environment. The significant associations between rate of single words and gesture + word combinations with language development over a year later have implications for incorporating intervention targets that encourage the use of gesture-speech combinations.

Project description: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.

Dataset Information

Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.

Publications

Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.

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