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.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating (PTV), missense, and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 ASD risk genes at false discovery rate (FDR)≤0.001 (185 at FDR≤0.05). De novo PTVs, damaging missense variants, and CNVs represented 57.5%, 21.1%, and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD, N=91,605) yielded 373 ASD/DD risk genes at FDR≤0.001 (664 at FDR≤0.05), some of which differed in relative frequency of mutation between ASD and DD. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells whereas genes displaying stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophreniaassociated genes, emphasizing that these neuropsychiatric disorders share common pathways to risk.

During sleep, the hippocampus plays an active role in consolidating memories that depend on it for initial encoding. There are hints in the literature that the hippocampus may have a broader influence, contributing to the consolidation of memories that may not initially require the area. We tested this possibility by evaluating learning and consolidation of the motor sequence task (MST) in hippocampal amnesics and demographically matched control participants. While the groups showed similar initial learning, only controls exhibited evidence of overnight consolidation. These results demonstrate that the hippocampus can be required for normal consolidation of a task without being required for its acquisition, suggesting that the area plays a broader role in coordinating memory consolidation than has previously been assumed.

The sixth meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) consortium was focused on selecting promising imaging biomarker measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of working memory (WM), the 2 constructs of interest were "goal maintenance" and "interference control." CNTRICS received 7 task nominations for goal maintenance and 3 task nominations for interference control. For goal maintenance, the breakout group for WM recommended the AX Continuous Performance Test/Dot Pattern Expectancy (DPX) and the Switching Stroop task for translation and further development for use in clinical trial contexts in schizophrenia research. Notably, these same 2 paradigms were recommended for "rule generation and selection" in executive control, a highly related construct. For interference control, the breakout group recommended the Suppress Task and the Sternberg Item Recognition Paradigm for translation for use in clinical trials. This manuscript describes the ways in which each of these tasks met the criteria used by the breakout group to recommend tasks for further development. In addition, the group revisited the construct of WM capacity. Since the initial CNTRICS meeting, a growing body of work has emerged on the neurobiological substrates of WM capacity, making measure of this construct ready for translation. The group suggested a promising imaging biomarker measure for capacity, a version of the change detection task that measures delay activity over posterior parietal and occipital cortex.