Homozygous HLA-DQB1*06:02 combined with T-cell receptor alpha polymorphism results in narcolepsy onset - A familial case report.

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank.

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Genome-wide association study identifies 74 loci associated with educational attainment.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Systematic review of associations between HLA and renal function.

INTRODUCTION: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations. METHODS: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study. RESULTS: A total of 95 HLA types and 14 three-locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. DISCUSSION: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

OBJECTIVES: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death. METHODS/DESIGN: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD). RESULTS: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology. CONCLUSIONS: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.

Longitudinal sleep efficiency in the elderly and its association with health.

The relationships between older age and sleep efficiency have traditionally been assessed using cross-sectional studies that ignore changes within individuals as they age. This research examines the determinants of sleep efficiency, the heterogeneity in an individual's sleep efficiency trajectory across a period of up to 27 years in later life and its associations with health. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (n = 6,375; age 42-94 years) was used in this study. Depression and health data were collected using self-report validated instruments (Cornell Medical Index, Beck Depression Inventory and Geriatric Depression Scale). Longitudinal sleep and sociodemographic data were collected using a study-specific self-report questionnaire. A mixed-effect model was performed for sleep efficiency with adjustments for time-invariant and time-variant predictors. Latent class analysis was used to demonstrate subgroups of sleep efficiency trajectories and associations between sleep efficiency clusters and health history of the participants were investigated. Older adults have decreased sleep efficiency over time, with 18.6% decline between 40 and 100 years of age. Three sleep efficiency trajectory clusters were identified: high (32%), medium (50%) and low sleep efficiency (18%). Belonging to the high sleep efficiency cluster was associated with having lower prevalence of hypertension, circulatory problems, general arthritis, breathing problems and recurrent episodes of depression compared to the low efficiency cluster. Overall, ageing decreases sleep efficiency. However, there are detectable subgroups of sleep efficiency that are related to prevalence of different diseases.

Seasonality and season of birth effect in the UK Biobank cohort.

OBJECTIVES: Humans live in environments that reduce the impact of seasonal cues. However, studies suggest that many aspects of human biology, such as birth, metabolism, health, and death are still annually rhythmic. METHODS: Using UK Biobank, a large (N = 502 536) population-based resource, we investigated the influence of seasonality on birth rate, basal metabolic rate, health, reaction speed, and sleep. We also investigated the association between season of birth and regional brain volumes, basal metabolic rate, health, reaction speed, and sleep. RESULTS: Our results showed that annual birth rate peaks in April and May. Individuals had the highest basal metabolic rate in December and January. Poorer subjective general health and slower reaction time were observed in May. Susceptibility to insomnia showed an opposite trend that peaked in autumn and winter. People reported shorter periods of sleep, easier waking, earlier chronotype, more daytime dozing, and napping in summer compared with winter. Our results suggest that season of birth may influence later-life characteristics. We also observed that the effect of season of birth is in the opposite direction of the seasonal rhythm for basal metabolic rate, reaction time, and insomnia. Moreover, our analysis showed that prevalence of allergy is higher among people born in spring compared to autumn. CONCLUSIONS: Overall, our findings indicate a significant effect of seasonality on a range of human traits and that early-life seasons appear to have an effect on health and behaviors in adulthood.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

A role for HLA-DRB1*1101 and DRB1*0801 in cognitive ability and its decline with age.

Cognitive abilities (memory, processing speed, vocabulary, and fluid intelligence) are correlated with educational attainment and occupational status, as well as physical and mental health. The variation in cognitive abilities observed within a population has a substantial genetic contribution (heritability ∼50%) and yet the identification of genetic polymorphisms from both genome-wide association and candidate studies have to date only uncovered a limited number of genetic variants that exert small genetic effects. Here we impute human leukocyte antigens (HLA) using existing genome-wide association data from 1,559 non-pathological elderly volunteers who have been followed for changes in cognitive functioning between a 12- and 18-year period. Specifically, we investigate DRB1*05 (*11/*12) and DRB1*01, which have previously been associated with cognitive ability. We also analyze DRB1*0801, which shares close sequence homology with DRB1*1101. Together with DRB1*1101, DRB1*0801 has been associated with several diseases including multiple sclerosis and primary biliary cirrhosis, which themselves are associated with cognitive impairment. We observed that both DRB1*0801 and DRB1*1101 were significantly associated with vocabulary ability (cross-sectional and longitudinal scores) and that the effects were in opposite directions with DRB1*0801 associated with lower score and faster decline. This opposing affect is similar to that reported by other groups in systemic lupus erythematosus, type 1 diabetes, and primary biliary cirrhosis. DRB1*0801 was also significantly associated with reduced memory ability. We observed no associations between cognitive abilities and DRB1*01 or DRB1*12.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

Self-Reported Late-Life Hypertension Is Associated with a Healthy Cognitive Status and Reduced Alzheimer's Disease Pathology Burden.

Background: While mid-life hypertension represents a risk factor for the development of Alzheimer's disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria-even after controlling for sex, level of education and presence of APOEɛ4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1.

IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ~6-fold as compared with basal activity, and that containing the C allele by ~9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections.

Education mediating the associations between early life factors and frailty: a cross-sectional study of the UK Biobank.

OBJECTIVES: Exposures in utero and during infancy may impact the development of diseases later in life. They may be linked with development of frailty, although the mechanism is unclear. This study aims to determine the associations between early life risk factors and development of frailty among middle-aged and older adults as well as potential pathways via education, for any observed association. DESIGN: A cross-sectional study. SETTINGS: This study used data from UK Biobank, a large population-based cohort. PARTICIPANTS: 502 489 individuals aged 37-73 years were included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Early life factors in this study included being breast fed as a baby, maternal smoking, birth weight, the presence of perinatal diseases, birth month and birth place (in or outside the UK). We developed a frailty index comprising 49 deficits. We used generalised structural equation modelling to examine the associations between early life factors and development of frailty and whether any observed association was mediated via educational attainment. RESULTS: A history of breast feeding and normal birth weight were associated with a lower frailty index while maternal smoking, the occurrence of perinatal diseases and birth month with a longer day length were associated with a higher frailty index. Educational level mediated the relationship between these early life factors and frailty index. CONCLUSIONS: This study highlights that biological and social risk occurring at different stages of life are related to the variations in frailty index in later life and suggests opportunities for prevention across the life course.

Virtual reality in simulation-based emergency skills training: A systematic review with a narrative synthesis.

Objective: An important role is predicted for virtual reality (VR) in the future of medical education. We performed a systematic review of the literature with a narrative synthesis, to examine the current evidence for VR in simulation-based emergency skills training. We broadly define emergency skills as any clinical skill used in the emergency care of patients across all clinical settings. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The data sources accessed during this study included: PubMed, CINAHL, EMBASE, AMED, EMCARE, HMIC, BNI, PsychINFO, Medline, CENTRAL, SCOPUS, Web of Science, BIOSIS Citation Index, ERIC, ACM Digital Library, IEEE Xplore, and ProQuest Dissertations and Thesis Global. Cochrane's Rob 2 and ROBVIS tools were used during study quality assessment. No ethical review was required for this work. Results: Thirty-four articles published between 14th March 1998 and 1st March 2022 were included in this review. Studies were predominantly conducted in the USA and Europe and focussed on a variety of healthcare disciplines including medical, nursing, and allied health. VR education was delivered using head-mounted displays, Cave Automatic Virtual Environment systems, and bespoke setups. These systems delivered education in a variety of areas (emergency medicine, equipment training, obstetrics, and basic/advanced life support). Subjective potential advantages of this technology included realism, replayability, and time-effectiveness. Reports of adverse events were low in frequency across the included studies. Whilst clear educational benefit was generally noted, this was not reflected in changes to patient-based outcomes. Conclusion: There may be educational benefit to using VR in the context of simulation-based emergency skills training including knowledge gain and retention, skill performance, acceptability, usability, and validity. Currently, there is insufficient evidence to demonstrate clear cost-effectiveness, or direct improvement of patient or institutional outcomes, at this stage.