Genome-wide association studies and other discovery genetics methods provide a means to identify previously unknown biological mechanisms underlying behavioral disorders that may point to new ...therapeutic avenues, augment diagnostic tools, and yield a deeper understanding of the biology of psychiatric conditions. Recent advances in psychiatric genetics have been made possible through large-scale collaborative efforts. These studies have begun to unearth many novel genetic variants associated with psychiatric disorders and behavioral traits in human populations. Significant challenges remain in characterizing the resulting disease-associated genetic variants and prioritizing functional follow-up to make them useful for mechanistic understanding and development of therapeutics. Model organism research has generated extensive genomic data that can provide insight into the neurobiological mechanisms of variant action, but a cohesive effort must be made to establish which aspects of the biological modulation of behavioral traits are evolutionarily conserved across species. Scalable computing, new data integration strategies, and advanced analysis methods outlined in this review provide a framework to efficiently harness model organism data in support of clinically relevant psychiatric phenotypes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
TRIM9 and TRIM67 are neuronally enriched E3 ubiquitin ligases essential for appropriate morphogenesis of cortical and hippocampal neurons and fidelitous responses to the axon guidance cue netrin-1. ...Deletion of murine
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results in neuroanatomical defects and striking behavioral deficits, particularly in spatial learning and memory. TRIM9 and TRIM67 interact with cytoskeletal and exocytic proteins, but the full interactome is not known. Here we performed the unbiased proximity-dependent biotin identification (BioID) approach to define TRIM9 and TRIM67 protein-protein proximity network in developing cortical neurons and identified putative neuronal TRIM interaction partners. Candidates included cytoskeletal regulators, cytosolic protein transporters, exocytosis and endocytosis regulators, and proteins necessary for synaptic regulation. A subset of high-priority candidates was validated, including Myo16, Coro1A, MAP1B, ExoC1, GRIP1, PRG-1, and KIF1A. For a subset of validated candidates, we utilized total internal reflection fluorescence microscopy to demonstrate dynamic colocalization with TRIM proteins at the axonal periphery, including at the tips of filopodia. Further analysis demonstrated that the RNA interference-based knockdown of the unconventional myosin Myo16 in cortical neurons altered growth cone filopodia density and axonal branching patterns in a TRIM9- and netrin-1-dependent manner. Future analysis of other validated candidates will likely identify novel proteins and mechanisms by which TRIM9 and TRIM67 regulate neuronal form and function. Media: see text.
To describe how using a combined approach of community-based participatory research and intervention mapping principles could inform the development of a tailored complex intervention to improve ...management of asthma for South Asian (SA) children; Management and Interventions for Asthma (MIA) study.
A qualitative study using interviews, focus groups, workshops, and modified intervention mapping procedures to develop an intervention planning framework in an urban community setting in Leicester, UK. The modified form of intervention mapping (IM) included: systematic evidence synthesis; community study; families and healthcare professionals study; and development of potential collaborative intervention strategies. Participants in the community study were 63 SA community members and 12 key informants; in-depth semi-structured interviews involved 30 SA families, 14 White British (WB) families and 37 Healthcare Professionals (HCPs) treating SA children living with asthma; prioritisation workshops involved 145 SA, 6 WB and 37 HCP participants; 30 participants in finalisation workshops.
Two key principles were utilised throughout the development of the intervention; community-based participatory research (CBPR) principles and intervention mapping (IM) procedures. The CBPR approach allowed close engagement with stakeholders and generated valuable knowledge to inform intervention development. It accounted for diverse perceptions and experiences with regard to asthma and recognised the priorities of patients and their families/caregivers for service improvement. The 'ACT on Asthma' programme was devised, comprising four arms of an intervention strategy: education and training, clinical support, advice centre and raising awareness, to be co-ordinated by a central team.
The modified IM principles utilised in this study were systematic and informed by theory. The combined IM and participatory approach could be considered when tailoring interventions for other clinical problems within diverse communities. The IM approach to intervention development was however resource intensive. Working in meaningful collaboration with minority communities requires specific resources and a culturally competent methodology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Limited guidance exists regarding the assessment and management of psychogenic non‐epileptic seizures (PNES) in children. Our aim was to develop consensus‐based recommendations to fill this gap. The ...members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment—There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a “probable” diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management—There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities—There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Sleep problems and substance use frequently co‐occur. While substance use can result in specific sleep deficits, genetic pleiotropy could explain part of the relationship between sleep and substance ...use and use disorders. Here we use the largest publicly available genome‐wide summary statistics of substance use behaviours (N = 79,729–632,802) and sleep/activity phenotypes to date (N = 85,502–449,734) to (1) assess the genetic overlap between substance use behaviours and both sleep and circadian‐related activity measures, (2) estimate clusters from genetic correlations and (3) test processes of causality versus genetic pleiotropy. We found 31 genetic correlations between substance use and sleep/activity after Bonferroni correction. These patterns of overlap were represented by two genetic clusters: (1) tobacco use severity (age of first regular tobacco use and smoking cessation) and sleep health (sleep duration, sleep efficiency and chronotype) and (2) substance consumption/problematic use (drinks per day and cigarettes per day, cannabis use disorder, opioid use disorder and problematic alcohol use) and sleep problems (insomnia, self‐reported short sleep duration, increased number of sleep episodes, increased sleep duration variability and diurnal inactivity) and measures of circadian‐related activity (L5, M10 and sleep midpoint). Latent causal variable analyses determined that horizontal pleiotropy (rather than genetic causality) underlies a majority of the associations between substance use and sleep/circadian related measures, except one plausible genetically causal relationship for opioid use disorder on self‐reported long sleep duration. Results show that shared genetics are likely a mechanism that is at least partly responsible for the overlap between sleep and substance use traits.
We explored the genetic correlation and plausible correlation between several sleep and substance use phenotypes using genome‐wide association data and techniques. Sleep and substance use behaviors overlap due to genetic pleiotropy. There are two dimensions of sleep and substance use overlap: a sleep health and tobacco cluster (smoking cessation and initiation with sleep efficiency measures) and a sleep problem and heavy substance use cluster (insomnia, self‐reported sleep duration measures, and drinks per week).
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Because of widespread use, understanding the pulmonary effects of cannabis use is important; but its role independent from tobacco smoking is yet to be elucidated. We used Mendelian randomization ...(MR) to assess the effect of genetic liability to lifetime cannabis use and cannabis use disorder on pulmonary function and lung cancer.
We used four single nucleotide polymorphisms associated with lifetime cannabis use (p value <5 × 10−8) from a genome-wide association study (GWAS) of 184,765 individuals of European descent from the International Cannabis Consortium, 23andme, and U.K. Biobank as instrumental variables. Seven single nucleotide polymorphisms (p value <5 × 10−8) were selected as instruments for cannabis use disorder from a GWAS meta-analysis of 17,068 European ancestry cases and 357,219 controls of European descent from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative PsychiatricResearch, and deCode. To assess lung function, GWAS included 79,055 study participants of the SpiroMeta Consortium, and for lung cancer GWAS from the International Lung Cancer Consortium contained 29,266 cases and 56,450 controls.
MR revealed that genetic liability to lifetime cannabis use was associated with increased risk of squamous cell carcinoma (OR = 1.22, 95%, confidence interval = 1.07–1.39, p value = 0.003, q value = 0.025). Pleiotropy-robust methods and positive and negative control analyses did not indicate bias in the primary analysis.
The findings of this MR analysis suggest evidence for a potential causal association between genetic liability for cannabis use and the risk of squamous cell carcinoma. Triangulating MR and observational studies and addressing orthogonal sources of bias are necessary to confirm this finding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in ...understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (r g s = 0.17–0.62). Genetic instrumental variable analyses suggested the presence of shared heritable factors, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for these shared genetic factors. We identified 327 pleiotropic loci with 439 lead SNPs in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both shared genetic factors and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We surveyed UK and Republic of Ireland institutions to establish the extent of ultrasound use in teaching undergraduate modules with significant anatomy or physiology content. Responses indicate that ...although ultrasound is used for a wide variety of systems, only a small proportion of courses use ultrasound for teaching. There is widespread interest in its use, with the main barriers being unfamiliarity with potential uses and the technology. We endorse further dissemination of this teaching practice.
We have used ultrasound imaging and technology as a tool for nonclinical teaching of basic physiological concepts for several years and are aware anecdotally that only a few others in the United Kingdom and Republic of Ireland (UK/ROI) are also using ultrasound with this intention in physiology and anatomy teaching. To better understand what areas ultrasound is used for by others, along with what barriers might exist to its use, we reached out to colleagues in UK/ROI institutions instructing on anatomy and physiology courses by asking them to complete a survey regarding their experiences. Relatively few institutions (9%) reported using the technology in this way but covered physiology and anatomy teaching in most major body systems. The perception of responding educators overall is that, overwhelmingly, ultrasound offers a useful addition to the teaching of physiology and anatomy and is very popular with students. Barriers to its implementation were identified, including unfamiliarity with equipment and potential uses. Lack of funding for equipment and staff, issues with class sizes, and lack of curriculum time were also identified. Despite these potential impediments, most nonusers were interested in finding out about the uses of ultrasound as a teaching tool. We conclude that the teaching community would benefit from wider dissemination of local practices.
NEW & NOTEWORTHY We surveyed UK and Republic of Ireland institutions to establish the extent of ultrasound use in teaching undergraduate modules with significant anatomy or physiology content. Responses indicate that although ultrasound is used for a wide variety of systems, only a small proportion of courses use ultrasound for teaching. There is widespread interest in its use, with the main barriers being unfamiliarity with potential uses and the technology. We endorse further dissemination of this teaching practice.
Interpretations of time underlie patients' experiences of illness and the way in which the National Health Service (NHS) is organised. In the NHS, achieving short waiting times for treatment is seen ...as important, and this is particularly evident in relation to chronic conditions where the time waiting in care from onset of symptoms to successful management can last months and years. One example of a chronic condition with high prevalence is osteoarthritis, estimated to affect 10% of people aged over 55 years in the UK. Osteoarthritis of the hip is particularly common, and treatments include exercise and medication. If these options do not provide enough relief from pain and functional difficulties, then joint replacement may be considered. With over 70,000 such operations conducted every year in England and Wales, processes relating to waiting times impact on many patients. This article explores how 24 patients with osteoarthritis experience time during the lead up to hip replacement surgery. We draw on data collected during longitudinal in-depth interviews with patients a median of 9.5 days before surgery and at two to four weeks post-operatively. Transcripts of audio-recorded interviews were imported into Atlas.ti® and inductive thematic analysis undertaken. Increasing pain and deterioration in function altered the experience of time during the journey towards hip replacement. Patients made essential changes to how they filled their days. They experienced lost and wasted time and faced disruption to the temporal order of their lives. A surgical date marked in the calendar became their focus. However, this date was not static, moving because of changing perceptions of duration and real-time alterations by the healthcare system. Findings highlight that patients' experience of time is complex and multi-dimensional and does not reflect the linear, monochronic conceptualisation of time embedded in the healthcare system.
•Waiting for hip replacement disrupts the temporal order of patients' lives.•Patients' perceptions of time are multi-dimensional and complex.•Experiences of time differ from health services' monochronic construction of time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open ...reading frames (ORFs) occurs via RNA intermediates termed "subgenomic RNAs." sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5' UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5' end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6
+/- cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 samples worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.
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