Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Diagnostic stability at age 9 years was very high for autism at age 2 years and less strong for pervasive developmental disorder not otherwise specified. Judgment of experienced clinicians, trained on standard instruments, consistently added to information available from parent interview and standardized observation.

In the first half of this review, the authors critically evaluate existing research on the association between stressors and symptoms of psychopathology in children and adolescents. This analysis reveals (a) problems with conceptualizations of stress, (b) variability in measurement of stressors, and (c) lack of theory-driven research. To address these problems, the authors propose a general conceptual model of the relation between stressors and child and adolescent psychopathology. The authors examine basic tenets of this general model in the second half of this article by testing a specific model in which negative parenting mediates the relation between economic stressors and psychological symptoms in young people. Results generally provide support for the specific model as well as for the broader model.

This article reviews existing research on the association between stressors and symptoms of psychopathology in children and adolescents with a focus on measurement issues and prospective effects. The first half of the article focuses on the measurement of stressors, emphasizing checklists and interviews. Available measures of stressful experiences are reviewed and critiqued. Results of this review reveal both substantial progress (i.e., development of valid stressor assessment tools) and remaining problems (i.e., inconsistent measurement across studies). The second half of this article reviews studies that have tested for prospective associations between stressors and symptoms of psychopathology in children and adolescents. Studies that have examined the prospective effects of recent or prior stressors on current psychological symptoms, while controlling for prior psychological symptoms, are reviewed. Results overall suggest that stressors predict changes in rates of symptoms of psychopathology in children and adolescents over time. Results also suggest that symptoms of psychopathology predict changes in rates of stressors over time. Implications of these findings are that conclusive evidence now exists for the importance of stressors in the development of child and adolescent psychopathology.