A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with ...schizophrenia is uncertain.
To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.
We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.
We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader-Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10(-4)).
We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.
Background Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various ...congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. Methods We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. Results The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%. Conclusions CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling.
Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 ...schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.
“Ergonomic” is a common descriptor for a desk or computer workspace but is a term rarely used to describe a surgical instrument. Instead, surgeons spend many hours in inconvenient positions, often ...using instruments that are not ergonomic. Improving the ergonomics of surgical instruments may decrease the required force for simple tasks and allow for more efficient surgery.
To evaluate the impact of ergonomic surgical instruments, the authors developed ergonomic screwdriver handles. The shape and size of these handles were engineered using previous dental studies and 3-dimensional modeling to create an ideal handle for specific glove sizes. Participants were recruited to test 3 different ergonomic handle sizes against a standard screwdriver while assessing digital peak force, digital contact area, and participant preference. Ten participants (3 women) with glove sizes ranging from 6 to 8 were evaluated.
Ergonomic screwdriver handles sized for glove sizes 6 and 7 required significantly less thumb peak force than the standard screwdriver for all participants (702 N for glove size 6 and 567 N for glove size 7 ergonomic screwdrivers, vs 1780 N for “one size fits all” standard screwdriver). Participants consistently preferred screwdrivers that required lower thumb and index finger forces. All ergonomic handles required lower thumb and index finger force. Eighty percent of participants preferred a screwdriver modeled within 1 glove size of their own.
Improved ergonomic handles require less force and are preferred by surgeons.
The significant decrease in thumb peak force for glove sizes 6 and 7 suggests that there is room for ergonomic improvement in instruments, especially for surgeons with smaller hands. Manufacturing ergonomic screwdriver handles and using the evolving convenience of 3-dimensional printing may help to develop a more comfortable work environment for surgeons.
The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated ...characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.
This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.
A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.
Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.
Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms.
To identify components of genetic ...liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component.
Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022.
PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale.
Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania β = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10-25; psychosis β = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10-13) and the components that differentiate each of schizophrenia (mania β = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis β = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10-4) and BD (mania β = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10-7; psychosis β = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (β = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10-6) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (β = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (β = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (β = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (β = -0.11; 95% CI, -0.17 to -0.06; P = 7.06 × 10-5).
In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.
Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic "risk" and show how predictive modeling ...approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke's R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio OR = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome.
Schizophrenia typically onsets after puberty but is often preceded by observable childhood neurodevelopmental impairments. Whether these childhood antecedents index genetic liability is unknown. We ...used polygenic risk scores derived from a patient discovery sample as indicators of the genetic liability of schizophrenia. Our aim was to identify the early childhood manifestations of this liability in a UK population-based cohort.
The study sample was the Avon Longitudinal Study of Parents and Children, a prospective population-based cohort study of 14701 children. Data were primarily analysed with regression-based analyses. Polygenic risk score were generated from a published Psychiatric Genomics Consortium genome-wide association study. Outcomes were childhood (age 4-9 years) dimensional measures in four developmental domains with 12 indicators: cognition and learning, social and communication, emotion and mood regulation, and behaviour (n=5100-6952).
At age 7-9 years, schizophrenia polygenic risk scores showed associations with lower performance intelligence quotient (β -0·056, OR 1·13 95% CI 1·04-1·23), poorer social understanding (β -0·032, OR 1·08 1·00-1·17), worse language intelligibility and fluency (β -0·032, OR 1·10 1·02-1·20), more irritability (β 0·032, OR 1·07 1·01-1·14), and more headstrong behaviour (β 0·031, OR 1·08 1·02-1·15). The schizophrenia polygenic risk scores also predicted social and behavioural impairments as early as age 4 years.
Childhood cognitive, social, behavioural, and emotional impairments, implicated as antecedents to schizophrenia in high-risk, developmental studies, might represent early manifestations of genetic liability.
Medical Research Council.
There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.
We ...analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (
= 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (
= 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.
The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 relative excess risk due to interaction (RERI): 1.01,
= 0.037 and in EUGEI (RERI = 3.39,
= 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74,
= 0.003; EUGEI: RERI = 4.16,
= 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65,
= 0.284; EUGEI: -0.37,
= 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02,
< 0.001; EUGEI: 6.44,
< 0.001; RERI delusional ideation: NEMESIS-2: 3.79,
< 0.001; EUGEI: 5.43,
= 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46,
< 0.001; EUGEI: 0.54,
= 0.465).
The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
The Routledge Companion to African American Theatre and Performance is an outstanding collection of specially written essays that charts the emergence, development, and diversity of African American ...Theatre and Performance—from the nineteenth-century African Grove Theatre to Afrofuturism. Alongside chapters from scholars are contributions from theatre makers, including producers, theatre managers, choreographers, directors, designers, and critics. This ambitious Companion includes:A "Timeline of African American theatre and performance."Part I "Seeing ourselves onstage" explores the important experience of Black theatrical self-representation. Analyses of diverse topics including historical dramas, Broadway musicals, and experimental theatre allow readers to discover expansive articulations of Blackness.Part II "Institution building" highlights institutions that have nurtured Black people both on stage and behind the scenes. Topics include Historically Black Colleges and Universities (HBCUs), festivals, and black actor training.Part III "Theatre and social change" surveys key moments when Black people harnessed the power of theatre to affirm community realities and posit new representations for themselves and the nation as a whole. Topics include Du Bois and African Muslims, women of the Black Arts Movement, Afro-Latinx theatre, youth theatre, and operatic sustenance for an Afro future.Part IV "Expanding the traditional stage" examines Black performance traditions that privilege Black worldviews, sense-making, rituals, and innovation in everyday life. This section explores performances that prefer the space of the kitchen, classroom, club, or field.This book engages a wide audience of scholars, students, and theatre practitioners with its unprecedented breadth. More than anything, these invaluable insights not only offer a window onto the processes of producing work, but also the labour and economic issues that have shaped and enabled African American theatre.
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