Shorter sleep duration is associated with social impairment and comorbidities in ASD.

Sleep disturbance, particularly insomnia, is common in children with autism spectrum disorders (ASD). Furthermore, disturbed sleep affects core symptoms and other related comorbidities. Understanding the causes and consequences of sleep disturbances in children with ASD is an important step toward mitigating these symptoms. To better understand the connection between sleep duration and ASD severity, we analyzed ASD-related symptoms using the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), IQ scores, and parent reports of the average amount of time slept per night that were available in the medical histories of 2,714 children with ASD in the Simons Simplex Collection (SSC). The mean (SD) sleep duration was 555 minutes. Sleep duration and severity of core ASD symptoms were negatively correlated, and sleep duration and IQ scores were positively correlated. Regression results indicated that more severe social impairment, primarily a failure to develop peer relationships, is the core symptom most strongly associated with short sleep duration. Furthermore, increased severity for numerous maladaptive behaviors assessed on the Child Behavior Checklist, as well as reports of attention deficit disorder, depressive disorder, and obsessive compulsive disorder were associated with short sleep duration. Severity scores for social/communication impairment and restricted and repetitive behaviors (RRB) were increased, and IQ scores were decreased, for children reported to sleep ≤420 minutes per night (lower 5th percentile) compared to children sleeping ≥660 minutes (upper 95th percentile). Our results indicate that reduced amounts of sleep are related to more severe symptoms in children with ASD. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1221-1238. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.

BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-ß pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes.