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Background Methods Results Conclusions The Adolescent Brain Cognitive Development (ABCD) study is a longitudinal study of US adolescents with a wide breadth of psychiatric, neuroimaging and genetic data that can be leveraged to better understand psychiatric diseases. The reliability and validity of the psychiatric data collected have not yet been examined. This study aims to explore and optimize the reliability/validity of psychiatric diagnostic constructs in the ABCD study.Parent‐and‐child‐reported psychiatric data for 11,876 children (aged 9.5 ± 0.5 at first assessment) were examined over 4 years to derive specific constructs for psychiatric diagnoses using longitudinal information. Rates of psychiatric disorders were calculated and compared to those reported in the epidemiological literature.The rates of self‐reported psychiatric disorders at any single time point (broad diagnostic construct) were higher than indicated by epidemiological studies. Narrow diagnostic constructs, which required the endorsement of psychiatric disorders at a majority of longitudinal assessments, demonstrated a better rate approximation of literature‐reported prevalences for most disorders (e.g. the prevalence of broad obsessive‐compulsive disorder (OCD) was 13.3% compared to narrow OCD at 2.6% and a literature‐reported prevalence of 2.3%). Analysis of comorbidity, using OCD as a representative example, also showed a better approximation of literature‐reported comorbidity rates using the narrow construct, with some exceptions.Self‐ or parent‐report‐based assessments tend to overestimate prevalences of psychiatric disorders in the ABCD Study, particularly when longitudinal data are summed to create lifetime prevalences. Such assessments should be accompanied by more in‐depth assessments or clinician‐administered structured interviews if using data where accurate disorder classifications are paramount. [ABSTRACT FROM AUTHOR]

Background: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. Objective: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. Methods: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta‐analyses, incorporating data from previously published literature. Results: Rates of obsessive–compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta‐analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First‐degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. Conclusions: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

The thymus is a primary lymphoid organ that plays an essential role in T lymphocyte maturation and selection during development of one arm of the mammalian adaptive immune response. Although transcriptional mechanisms have been well documented in thymocyte development, co-/post-transcriptional modifications are also important but have received less attention. Here we demonstrate that the RNA alternative splicing factor MBNL1, which is sequestered in nuclear RNA foci by C(C)UG microsatellite expansions in myotonic dystrophy (DM), is essential for normal thymus development and function. Mbnl1 129S1 knockout mice develop postnatal thymic hyperplasia with thymocyte accumulation. Transcriptome analysis indicates numerous gene expression and RNA mis-splicing events, including transcription factors from the TCF/LEF family. CNBP, the gene containing an intronic CCTG microsatellite expansion in DM type 2 (DM2), is coordinately expressed with MBNL1 in the developing thymus and DM2 CCTG expansions induce similar transcriptome alterations in DM2 blood, which thus serve as disease-specific biomarkers. The activity of the RNA splicing factor MBNL1 is altered in myotonic dystrophy (DM) patients. Here the authors characterize the thymic phenotype of Mbnl1 knockout mice, including developmental defects, transcriptome changes, and RNA mis-splicing of transcripts encoding thymic transcription factors. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) may play a critical role in gene regulation in various diseases or biological processes by controlling post-transcriptional events such as polyadenylation, splicing and mRNA stabilization via binding activities to RNA molecules. Owing to the importance of RBPs in gene regulation, a great number of studies have been conducted, resulting in a large amount of RNA-Seq datasets. However, these datasets usually do not have structured organization of metadata, which limits their potentially wide use. To bridge this gap, the metadata of a comprehensive set of publicly available mouse RNA-Seq datasets with perturbed RBPs were collected and integrated into a database called RBPMetaDB. This database contains 292 mouse RNA-Seq datasets for a comprehensive list of 187 RBPs. These RBPs account for only ∼10% of all known RBPs annotated in Gene Ontology, indicating that most are still unexplored using high-throughput sequencing. This negative information provides a great pool of candidate RBPs for biologists to conduct future experimental studies. In addition, we found that DNA-binding activities are significantly enriched among RBPs in RBPMetaDB, suggesting that prior studies of these DNA- and RNA-binding factors focus more on DNA-binding activities instead of RNA-binding activities. This result reveals the opportunity to efficiently reuse these data for investigation of the roles of their RNA-binding activities. A web application has also been implemented to enable easy access and wide use of RBPMetaDB. It is expected that RBPMetaDB will be a great resource for improving understanding of the biological roles of RBPs. Database URL: http://rbpmetadb.yubiolab.org [ABSTRACT FROM AUTHOR]

Although the number of RNA-Seq datasets deposited publicly has increased over the past few years, incomplete annotation of the associated metadata limits their potential use. Because of the importance of RNA splicing in diseases and biological processes, we constructed a database called SFMetaDB by curating datasets related with RNA splicing factors. Our effort focused on the RNA-Seq datasets in which splicing factors were knocked-down, knocked-out or over-expressed, leading to 75 datasets corresponding to 56 splicing factors. These datasets can be used in differential alternative splicing analysis for the identification of the potential targets of these splicing factors and other functional studies. Surprisingly, only ~15% of all the splicing factors have been studied by loss- or gain-of-function experiments using RNA-Seq. In particular, splicing factors with domains from a few dominant Pfam domain families have not been studied. This suggests a significant gap that needs to be addressed to fully elucidate the splicing regulatory landscape. Indeed, there are already mouse models available for ~20 of the unstudied splicing factors, and it can be a fruitful research direction to study these splicing factors in vitro and in vivo using RNA-Seq. [ABSTRACT FROM AUTHOR]

Tourette syndrome (TS) is an early-onset neurodevelopmental disorder (NDD) characterized by vocal and motor tics. TS is highly heritable (60-80%) and has a complex genetic architecture with both rare and common variants contributing to the genetic etiology. However, the contribution of de novo mutations (DNMs) has not been widely studied due to the lack of large-scale high-quality family-structured sequencing datasets and insufficient statistical power. In this study, we generated whole-exome sequencing (WES) data for over 1,300 TS trio families and jointly called the data with a selected subset of over 6,600 families from SSC and SPARK datasets containing at least one Autism Spectrum Disorder (ASD) proband and an unaffected sibling. This produced a high-quality unified dataset with 30,803 individuals and 4,425,974 variants. Our principal component analysis showed a diverse ancestry background with all major population groups present in the ASD cohorts, while only European and Admixed American ancestries were present in the TS cohort. Analyzing samples from all three cohorts demonstrated a significant exome-wide enrichment of DNMs, in the category of protein-truncating variants (PTVs) and damaging missense variants (Dmis), in TS probands compared to healthy controls, while confirming a significant enrichment of DNMs in ASD probands compared to healthy controls. The enrichment was further increased when we focused on genes with high pLI scores, indicating an impact of DNMs on the core body functionalities. To compare the genetic architecture of TS and ASD, we obtained genesets known to be associated with ASD and DD and confirmed a significant enrichment of DNMs in ASD probands compared to healthy controls, while TS probands only demonstrated a trend of enrichment in DD genes. Interestingly, when we looked at non-ASD genes, both TS probands and ASD probands from the SPARK cohort demonstrated significant enrichments of DNMs, suggesting a different genetic architecture between TS and ASD, while also recapitulating the potential phenotypic heterogeneity within the SPARK cohort. Lastly, to identify TS risk genes, we performed transmitted-and-de-novo-analysis (TADA) and identified three significant genes with FDR<0.05. In brief, our study includes one of the largest TS-ASD WES family datasets that will facilitate future genetic and clinical studies on TS and comorbidities with improved power. Moreover, our work provides evidence of the contribution of de novo mutations to TS etiology, shows a different genetic architecture between TS and ASD, and pinpointed three TS risk genes. Further studies will focus on bridging rare variant effects to polygenic scores to boost modeling accuracy and dissect the heterogeneity in the SPARK cohort for improved statistical power. [ABSTRACT FROM AUTHOR]