Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Parenting stress in caregivers of young children with concerns about ASD prior to a formal diagnostic evaluation

Thesis (Master's)--University of Washington, 2019Robust findings demonstrate that parents of children with autism spectrum disorder (ASD) experience high levels of parenting stress that are related to negative outcomes for families. Although the majority of research on parenting stress has focused on parents of children with a current ASD diagnosis, parents of young children with concerns about ASD-related behaviors also face many unique challenges before the child receives a formal ASD diagnostic evaluation. However, no study to date has examined patterns of parenting stress among parents of children with ASD concerns prior to a formal ASD diagnosis. Therefore, the current study investigated longitudinal trajectories of parenting stress among parents of young children with ASD concerns compared to parents of children with non-ASD developmental concerns (e.g., language delay), and parents of children with no developmental concerns. Known predictors of parenting stress were also examined. Results revealed that parents of children with ASD concerns experienced consistently higher levels of parenting stress across early child development compared to parents of children with non-ASD developmental concerns and children with no concerns. Additionally, parenting efficacy, parent psychological functioning, parent social quality of life, and child social communication behaviors predicted levels of parenting stress for all parents

Outcomes among caregivers of toddlers with ASD concerns following implementation of Screen-Refer-Treat, a novel service delivery model for early ASD detection and intervention

Thesis (Ph.D.)--University of Washington, 2022The American Academy of Pediatrics recommends early ASD screening in primary care settings (Hyman et al., 2020) and evidence demonstrates that specialized early interventions lead to more optimal outcomes among children with ASD (Landa, 2018). However, rates of early ASD screening in the community remain low and many families face barriers to getting an ASD diagnostic evaluation and access to specialized intervention services. As such, caregivers report that the pre-diagnosis period is marked by uncertainty and overwhelming worry (Mulligan, MacCulloch, Good, & Nicholas, 2012), and previous research suggests a link between caregiver wellbeing and the quality of care services for children with ASD (Parker & Killian, 2020). To address these challenges, ongoing implementation efforts are aimed at increasing ASD screening and evidence-based early interventions in the community (Broder Fingert et al., 2019). Aligned with these efforts, a novel service delivery model, Screen-Refer-Treat (SRT; Ibañez et al, 2019), was developed and implmemented in 4 Washington State counties to increase use of the M-CHAT-R/F (Robins et al., 2014) at 18-month well-child primary care visits and expedite delivery of ASD early intervention (i.e., Reciprocal Imitation Training; Ingersoll, 2010) within Part C early intervention (EI) programs for toddlers who screen at-risk for ASD, but who have not yet received a formal ASD diagnostic evaluation. To implement SRT, primary care providers and EI providers received training on SRT components. Two separate cohorts of families were recruited - one before providers received SRT training and one following SRT training - to assess family outcomes before and after SRT was implemented. Families either had a child with ASD concerns (ASD-C), non-ASD developmental concerns (e.g., motor delays, DEV-C), or no developmental concerns (NO-C). The present study compared caregiver quality of life, parenting stress, parenting self-efficacy, and family-centered care between ASD-C, DEV-C, and NO-C caregivers who were either exposed (i.e., post-SRT cohort) or not exposed to SRT (i.e., pre-SRT cohort). Parenting self-efficacy and family-centered care did not differ between the three groups of caregivers or between the pre-SRT and post-SRT cohorts. Consistent with previous work (DesChamps, Ibañez, Edmunds, Dick, & Stone, 2020), results revealed that ASD-C caregivers in both cohorts reported higher levels of parenting stress compared to DEV-C and NO-C caregivers. Within the pre-SRT cohort, ASD-C caregivers reported lower quality of life compared to DEV-C and NO-C caregivers. However, quality of life was higher among ASD-C caregivers in the post-SRT cohort such that there was no longer a difference in quality of life among ASD-C, DEV-C, and NO-C caregivers following SRT implementation. This study provides preliminary evidence that implementation of the SRT service delivery model may have a positive impact on the wellbeing of caregivers of young children with ASD concerns. Results and limitations are further discussed

Additional file 1: of Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism

Clinical characterization for children with ASD is provided. Abbreviations: M, male; F, female; LGD, likely gene-disrupting; +, present; -, absent; NC, not completed. (XLS 47 kb

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

International audienceBackground: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.Methods: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.Results: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.Conclusions: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria