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Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
Objective: This study examines the interrelations of parenting practices, emotional climate, and household chaos in families with children with and without ADHD. In particular, indirect pathways from children’s ADHD symptomatology to inadequate parenting and negative emotional climate via household chaos were investigated. Method: Parenting, emotional climate, and household chaos were assessed using questionnaires and a speech sample of parents of 31 children with and 53 without ADHD, aged 7 to 13 years. Results: Group differences were found for certain parenting dimensions, the parent–child relationship, critical comments, and household chaos. While we found significant indirect effects between children’s ADHD and certain parenting dimensions through household chaos, no effects were found for any aspect of emotional climate. Conclusion: Children’s ADHD symptoms translate into inadequate parenting through household chaos, which underlines the need for interventions to improve household organization skills in parents of children with ADHD.
Abstract: The Children's Communication Checklist-2 (CCC-2) is often applied to assess pragmatic language impairment which is highly prevalent in autism spectrum disorder (ASD) and several mental health conditions. We replicated previous findings on the limited applicability of the CCC-2 in clinical samples and the inconsistent findings concerning the factor structure. The aim of the present study was, thus, to develop a concise, simplified, and revised version of the CCC-2 in a large German-speaking sample. Four groups of children and adolescents aged 4 to 17 years were included: ASD (n = 195), intellectual disability (ID, n = 83), diverse mental health conditions (MHC, n = 144) and a typically developing control group (TD, n = 417). We reduced the original number of items from 70 to 39, based on item analysis, exploratory factor analysis and the exclusion of communication-unrelated items. The revised version, CCC-R (α = 0.96), consists of two empirically derived factors: a pragmatic-language (α = 0.96) and a grammatical-semantic-language factor (α = 0.93). All clinical groups (ASD, ID, and MHC) had significantly increased CCC-R total scores, with the highest scores being in the neurodevelopmental disorder groups (ASD and ID). In addition, we found group-specific patterns of elevated pragmatic-language scores in the ASD group and grammatical-semantic scores in the ID group. The CCC-R was comparable to the CCC-2 in distinguishing ASD from the other groups. The CCC-R is proposed as a simplified and easily applied, clinical questionnaire for caregivers, assessing pragmatic language impairments across neurodevelopmental disorders and mental health conditions. Lay Summary: The CCC-2 is a questionnaire designed to identify children who have problems in the social use of language, however, it is limited in its clinical application and exhibits inconsistent factors. We have created a shorter and simpler version of the CCC-2 that we have called the CCC-R which overcomes the previous limitations of the CCC-2. It consists of two subscales: pragmatic language and grammatical-semantic language. The CCC-R can be used as a short and clinically relevant caregiver questionnaire which assesses pragmatic language impairments in children and adolescents. Autism Res 2021, 14: 759–772. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.
Background: This article reports reliability, validity, and norms for the German version of the multi-informant questionnaire Inventory of Callous–Unemotional Traits (ICU). Method: The ICU was filled in by nonreferred children aged 13 to 18 years old (n = 645), parents of children aged 6 to 18 years old (n = 1,005), and their teachers (n = 955). Results: Confirmatory factor analysis resulted in a two-factor solution giving the best fit. Still none of the models showed an adequate model-fit applying the chi-square exact fit test. The internal consistency of the parent’s, teacher’s, and self-report version were α = .830, α = .877 and α = .769, respectively. Interrater reliability was moderate. Convergent validity with the Youth Psychopathic Traits Inventory, the externalizing scores of the Youth Self-Report/Child Behavior Checklist, and with the German oppositional Defiant Disorder/Conduct Disorder Rating Scale “FBB-SSV” were good. German norms were calculated. Conclusions: The ICU is a reliable and valid dimensional measure to describe callous–unemotional traits.
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Intention attribution in children and adolescents with autism spectrum disorder: an EEG study
(2021)
The ability to infer intentions from observed behavior and predict actions based on this inference, known as intention attribution (IA), has been hypothesized to be impaired in individuals with autism spectrum disorder (ASD). The underlying neural processes, however, have not been conclusively determined. The aim of this study was to examine the neural signature of IA in children and adolescents with ASD, and to elucidate potential links to contextual updating processes using electroencephalography. Results did not indicate that IA or early contextual updating was impaired in ASD. However, there was evidence of aberrant processing of expectation violations in ASD, particularly if the expectation was based on IA. Results are discussed within the context of impaired predictive coding in ASD.
Objective: Studies using diffusion tensor imaging (DTI) to investigate white matter (WM) microstructure in youths with conduct disorder (CD) have reported disparate findings. We investigated WM alterations in a large sample of youths with CD, and examined the influence of sex and callous-unemotional (CU) traits.
Method: DTI data were acquired from 124 youths with CD (59 female) and 174 typically developing (TD) youths (103 female) 9 to 18 years of age. Tract-based spatial statistics tested for effects of diagnosis and sex-by-diagnosis interactions. Associations with CD symptoms, CU traits, a task measuring impulsivity, and the impact of comorbidity, and age- and puberty-related effects were examined.
Results: Youths with CD exhibited higher axial diffusivity in the corpus callosum and lower radial diffusivity and mean diffusivity in the anterior thalamic radiation relative to TD youths. Female and male youths with CD exhibited opposite changes within the internal capsule, fornix, posterior thalamic radiation, and uncinate fasciculus. Within the CD group, CD symptoms and callous traits exerted opposing influences on corpus callosum axial diffusivity, with callous traits identified as the unique clinical feature predicting higher axial diffusivity and lower radial diffusivity within the corpus callosum and anterior thalamic radiation, respectively. In an exploratory analysis, corpus callosum axial diffusivity partially mediated the association between callous traits and impulsive responses to emotional faces. Results were not influenced by symptoms of comorbid disorders, and no age- or puberty-related interactions were observed.
Conclusion: WM alterations within the corpus callosum represent a reliable neuroimaging marker of CD. Sex and callous traits are important factors to consider when examining WM in CD.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N = 189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous-unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability.