Developmental course of autistic social impairment in males

Washington University School of Medicine, St. Louis, MO 63110, USA.
Development and Psychopathology (Impact Factor: 4.89). 02/2009; 21(1):127-38. DOI: 10.1017/S095457940900008X
Source: PubMed

ABSTRACT Recent research has suggested that autistic social impairment (ASI) is continuously distributed in nature and that subtle autistic-like social impairments aggregate in the family members of children with pervasive developmental disorders (PDDs). This study examined the longitudinal course of quantitatively characterized ASI in 3- to 18-year-old boys with and without PDD. We obtained assessments of 95 epidemiologically ascertained male-male twin pairs and a clinical sample of 95 affected children using the Social Responsiveness Scale (SRS), at two time points, spaced 1-5 years apart. Longitudinal course was examined as a function of age, familial loading for PDD, and autistic severity at baseline. Interindividual variation in SRS scores was highly preserved over time, with test-retest correlation of 0.90 for the entire sample. SRS scores exhibited modest general improvement over the study period; individual trajectories varied as a function of severity at baseline and were highly familial. Quantitative measurements of ASI reflect heritable traitlike characteristics. Such measurements can serve as reliable indices of phenotypic severity for genetic and neurobiologic studies, and have potential utility for ascertaining incremental response to intervention.

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Available from: Teddi Gray, May 15, 2014
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    • "Autism spectrum disorders (ASDs) demarcate the extreme end of a continuum of behavioural difficulties [1], characterised by impairments of social interaction and communication as well as highly restricted interests and/or stereotyped repetitive behaviours [2]. The subthreshold end of this continuum is embodied by ASD-related but milder and non-psychopathological phenotypes, which are, as ASD, highly heritable (h2 = 0.36 to 0.87 [3-9]) and highly persistent [10,11] throughout the course of development. "
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    ABSTRACT: 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 < P-replication <=0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.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.
    Molecular Autism 09/2013; 4(1):34. DOI:10.1186/2040-2392-4-34 · 5.41 Impact Factor
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    • "Importantly, we did not find a significant effect of age; the anatomically distinct cortical correlates of autistic and antisocial traits, previously shown to be temporally stable using the SRS (Constantino et al., 2009) and APSD (Muñoz and Frick, 2007), appeared early and held throughout childhood, adolescence, and young adulthood. Thus fixed, distinct neuroanatomic signatures emerge, predominantly superior temporal/temporo-parietal thinning for autistic traits and primarily anterior prefrontal cortical thinning for antisocial traits. "
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    ABSTRACT: In humans, behaviors associated with autism and antisociality, disorders characterized by distinct social impairments, can be viewed as quantitative traits that range from frank impairment to normal variation, as found in the general population. Neuroimaging investigations of autism and antisociality demonstrate diagnostically specific aberrant cortical brain structure. However, little is known about structural brain correlates of social behavior in nonclinical populations. Therefore, we sought to determine whether autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. Three hundred twenty-three typically developing youth (age at first scan: mean = 10.63, SD = 3.71 years) underwent anatomic magnetic resonance imaging (1-6 scans each; total = 742 scans), and provided ratings of autistic and antisocial traits. Higher autistic trait ratings were associated with thinner cortex most prominently in right superior temporal sulcus while higher antisocial trait ratings were associated with thinner cortex in primarily bilateral anterior prefrontal cortices. There was no interaction with age, indicating that these brain-behavior associations were stable across development. Using assessments of both subclinical autistic and subclinical antisocial traits within a large longitudinal sample of typically developing youth, we demonstrate dissociable neuroanatomic correlations that parallel those found in the frank clinical disorders of autism (e.g., superior temporal cortex) and antisociality (e.g., anterior prefrontal cortex). Moreover, these correlations appear to be established in early childhood and remain fixed into early adulthood. These results support the dimensional view of psychopathology and provide neural signatures that can serve as informative endophenotypes for future genetic studies.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(14):4856-60. DOI:10.1523/JNEUROSCI.6214-11.2012 · 6.34 Impact Factor
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    • "For each marker, the location on chromosome 3 and the distance from the transcription start (TrxSt) site of OXTR are indicated . Also listed is whether the marker was genotyped by the Levitt lab in-house using Taqman assays or by the Broad Institute using the Affymetrix 5.0 GWAS platform both parent and teacher scales, the SRS T scores were averaged from all available informants (Constantino et al. 2009 "
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    ABSTRACT: Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.
    Journal of Neurodevelopmental Disorders 06/2011; 3(2):101-12. DOI:10.1007/s11689-010-9071-2 · 3.27 Impact Factor
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