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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]

Background: The Populations Underrepresented in Mental illness Association Studies (PUMAS) project is attempting to remediate the historical underrepresentation of African and Latin American populations in psychiatric genetics through large-scale genetic association studies of individuals diagnosed with a serious mental illness [SMI, including schizophrenia (SCZ), schizoaffective disorder (SZA) bipolar disorder (BP), and severe major depressive disorder (MDD)] and matched controls. Given growing evidence indicating substantial symptomatic and genetic overlap between these diagnoses, we sought to enable transdiagnostic genetic analyses of PUMAS data by conducting phenotype alignment and harmonization for 89,320 participants (48,165 cases and 41,155 controls) from four cohorts, each of which used different ascertainment and assessment methods: PAISA n=9,105; PUMAS-LATAM n=14,638; NGAP n=42,953 and GPC n=22,624. As we describe here, these efforts have yielded harmonized datasets enabling us to analyze PUMAS genetic variation data at three levels: SMI overall, diagnoses, and individual symptoms., Methods: In aligning item-level phenotypes obtained from 14 different clinical instruments, we incorporated content, branching nature, and time frame for each phenotype; standardized diagnoses; and selected 19 core SMI item-level phenotypes for analyses. The harmonization was evaluated in PUMAS cases using multiple correspondence analysis (MCA), co-occurrence analyses, and item-level endorsement., Outcomes: We mapped >6,895 item-level phenotypes in the aggregated PUMAS data, in which SCZ (44.97%) and severe BP (BP-I, 31.53%) were the most common diagnoses. Twelve of the 19 core item-level phenotypes occurred at frequencies of > 10% across all diagnoses, indicating their potential utility for transdiagnostic genetic analyses. MCA of the 14 phenotypes that were present for all cohorts revealed consistency across cohorts, and placed MDD and SCZ into separate clusters, while other diagnoses showed no significant phenotypic clustering., Interpretation: Our alignment strategy effectively aggregated extensive phenotypic data obtained using diverse assessment tools. The MCA yielded dimensional scores which we will use for genetic analyses along with the item level phenotypes. After successful harmonization, residual phenotypic heterogeneity between cohorts reflects differences in branching structure of diagnostic instruments, recruitment strategies, and symptom interpretation (due to cultural variation).

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTG exp ) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTG exp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1., (© 2019 Nutter et al.; Published by Cold Spring Harbor Laboratory Press.)