We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure coreplatform@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Studies have reported mixed findings regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women and birth outcomes. This study used a quasi-experimental design to account for potential confounding by sociodemographic characteristics.
Methods
Data were drawn from 16 prenatal cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) program. Women exposed to the pandemic (delivered between 12 March 2020 and 30 May 2021) (n = 501) were propensity-score matched on maternal age, race and ethnicity, and child assigned sex at birth with 501 women who delivered before 11 March 2020. Participants reported on perceived stress, depressive symptoms, sedentary behavior, and emotional support during pregnancy. Infant gestational age (GA) at birth and birthweight were gathered from medical record abstraction or maternal report.
Results
After adjusting for propensity matching and covariates (maternal education, public assistance, employment status, prepregnancy body mass index), results showed a small effect of pandemic exposure on shorter GA at birth, but no effect on birthweight adjusted for GA. Women who were pregnant during the pandemic reported higher levels of prenatal stress and depressive symptoms, but neither mediated the association between pandemic exposure and GA. Sedentary behavior and emotional support were each associated with prenatal stress and depressive symptoms in opposite directions, but no moderation effects were revealed.
Conclusions
There was no strong evidence for an association between pandemic exposure and adverse birth outcomes. Furthermore, results highlight the importance of reducing maternal sedentary behavior and encouraging emotional support for optimizing maternal health regardless of pandemic conditions.
Multi-messenger observations of the transient sky to detect cosmic explosions and counterparts of gravitational wave mergers critically rely on orbiting wide-FoV telescopes to cover the wide range of wavelengths where atmospheric absorption and emission limit the use of ground facilities. Thanks to continuing technological improvements, miniaturised space instruments operating as distributed-aperture constellations are offering new capabilities for the study of high-energy transients to complement ageing existing satellites. In this paper we characterise the performance of the upcoming joint SpIRIT and HERMES-TP/SP constellation for the localisation of high-energy transients through triangulation of signal arrival times. SpIRIT is an Australian technology and science demonstrator satellite designed to operate in a low-Earth Sun-synchronous Polar orbit that will augment the science operations for the equatorial HERMES-TP/SP constellation. In this work we simulate the improvement to the localisation capabilities of the HERMES-TP/SP constellation when SpIRIT is included in an orbital plane nearly perpendicular (inclination = 97.6°) to the HERMES-TP/SP orbits. For the fraction of GRBs detected by three of the HERMES satellites plus SpIRIT, we find that the combined constellation is capable of localising 60% of long GRBs to within
${\sim}30\,\textrm{deg}^{2}$
on the sky, and 60% of short GRBs within
${\sim}1850\,\textrm{deg}^{2}$
(
$1\sigma$
confidence regions), though it is beyond the scope of this work to characterise or rule out systematic uncertainty of the same order of magnitude. Based purely on statistical GRB localisation capabilities (i.e., excluding systematic uncertainties and sky coverage), these figures for long GRBs are comparable to those reported by the Fermi Gamma Burst Monitor instrument. These localisation statistics represents a reduction of the uncertainty for the burst localisation region for both long and short GRBs by a factor of
${\sim}5$
compared to the HERMES-TP/SP alone. Further improvements by an additional factor of 2 (or 4) can be achieved by launching an additional 4 (or 6) SpIRIT-like satellites into a Polar orbit, respectively, which would both increase the fraction of sky covered by multiple satellite elements, and also enable localisation of
${\geq} 60\%$
of long GRBs to within a radius of
${\sim}1.5^{\circ}$
(statistical uncertainty) on the sky, clearly demonstrating the value of a distributed all-sky high-energy transient monitor composed of nano-satellites.
A machine learning model was created to predict the electron spectrum generated by a GeV-class laser wakefield accelerator. The model was constructed from variational convolutional neural networks, which mapped the results of secondary laser and plasma diagnostics to the generated electron spectrum. An ensemble of trained networks was used to predict the electron spectrum and to provide an estimation of the uncertainty of that prediction. It is anticipated that this approach will be useful for inferring the electron spectrum prior to undergoing any process that can alter or destroy the beam. In addition, the model provides insight into the scaling of electron beam properties due to stochastic fluctuations in the laser energy and plasma electron density.
Long-duration gamma-ray burst (GRB) afterglow observations offer cutting-edge opportunities to characterise the star formation history of the Universe back to the epoch of reionisation, and to measure the chemical composition of interstellar and intergalactic gas through absorption spectroscopy. The main barrier to progress is the low efficiency in rapidly and confidently identifying which bursts are high redshift (
$z > 5$
) candidates before they fade, as this requires low-latency follow-up observations at near-infrared wavelengths (or longer) to determine a reliable photometric redshift estimate. Since no current or planned gamma-ray observatories carry near-infrared telescopes on-board, complementary facilities are needed. So far this task has been performed by instruments on the ground, but sky visibility and weather constraints limit the number of GRB targets that can be observed and the speed at which follow-up is possible. In this work we develop a Monte Carlo simulation framework to investigate an alternative approach based on the use of a rapid-response near-infrared nano-satellite, capable of simultaneous imaging in four bands from
$0.8$
to
$1.7\,\unicode{x03BC}$
m (a mission concept called SkyHopper). Using as reference a sample of 88 afterglows observed with the GROND instrument on the MPG/ESO telescope, we find that such a nano-satellite is capable of detecting in the H-band (1.6
$\unicode{x03BC}$
m)
$72.5\% \pm 3.1\%$
of GRBs concurrently observable with the Swift satellite via its UVOT instrument (and
$44.1\% \pm 12.3\%$
of high redshift (
$z>5$
) GRBs) within 60 min of the GRB prompt emission. This corresponds to detecting
${\sim}55$
GRB afterglows per year, of which 1–3 have
$z > 5$
. These rates represent a substantial contribution to the field of high-z GRB science, as only 23
$z > 5$
GRBs have been collectively discovered by the entire astronomical community over the last
${\sim}24$
yr. Future discoveries are critically needed to take advantage of next generation follow-up spectroscopic facilities such as 30m-class ground telescopes and the James Webb Space Telescope. Furthermore, a systematic space-based follow-up of afterglows in the near-infrared will offer new insight on the population of dusty (‘dark’) GRBs which are primarily found at cosmic noon (
$z\sim 1-3$
). Additionally, we find that launching a mini-constellation of 3 near-infrared nano-satellites would increase the detection fraction of afterglows to
${\sim}83\%$
and substantially reduce the latency in the photometric redshift determination.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.
Palmer amaranth (Amaranthus palmeri S. Watson) is one of the most problematic weeds in many cropping systems in the midsouthern United States because of its multiple weedy traits and its propensity to evolve resistance to many herbicides with different mechanisms of action. In Arkansas, A. palmeri has evolved metabolic resistance to S-metolachlor, compromising the effectiveness of an important weed management tool. Greenhouse studies were conducted to evaluate the differential response of A. palmeri accessions from three states (Arkansas, Mississippi, and Tennessee) to (1) assess the occurrence of resistance to S-metolachlor among A. palmeri populations, (2) evaluate the resistance level in selected accessions and their resistant progeny, (3) and determine the susceptibility of most resistant accessions to other soil-applied herbicides. Seeds were collected from 168 crop fields between 2017 and 2019. One hundred seeds per accession were planted in silt loam soil without herbicide for >20 yr and sprayed with the labeled rate of S-metolachlor (1,120 g ai ha−1). Six accessions (four from Arkansas and two from Mississippi) were classified resistant to S-metolachlor. The effective doses (LD50) to control the parent accessions ranged between 73 and 443 g ha−1, and those of F1 progeny of survivors were 73 to 577 g ha−1. The resistance level was generally greater among progeny of surviving plants than among resistant field populations. The resistant field populations required 2.2 to 7.0 times more S-metolachlor to reduce seedling emergence 50%, while the F1 of survivors needed up to 9.2 times more herbicide to reduce emergence 50% compared with the susceptible standard.
To examine differences in surgical practices between salaried and fee-for-service (FFS) surgeons for two common degenerative spine conditions. Surgeons may offer different treatments for similar conditions on the basis of their compensation mechanism.
Methods:
The study assessed the practices of 63 spine surgeons across eight Canadian provinces (39 FFS surgeons and 24 salaried) who performed surgery for two lumbar conditions: stable spinal stenosis and degenerative spondylolisthesis. The study included a multicenter, ambispective review of consecutive spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network registry between October 2012 and July 2018. The primary outcome was the difference in type of procedures performed between the two groups. Secondary study variables included surgical characteristics, baseline patient factors, and patient-reported outcome.
Results:
For stable spinal stenosis (n = 2234), salaried surgeons performed statistically fewer uninstrumented fusion (p < 0.05) than FFS surgeons. For degenerative spondylolisthesis (n = 1292), salaried surgeons performed significantly more instrumentation plus interbody fusions (p < 0.05). There were no statistical differences in patient-reported outcomes between the two groups.
Conclusions:
Surgeon compensation was associated with different approaches to stable lumbar spinal stenosis and degenerative lumbar spondylolisthesis. Salaried surgeons chose a more conservative approach to spinal stenosis and a more aggressive approach to degenerative spondylolisthesis, which highlights that remuneration is likely a minor determinant in the differences in practice of spinal surgery in Canada. Further research is needed to further elucidate which variables, other than patient demographics and financial incentives, influence surgical decision-making.
The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.
Patients with Duchenne muscular dystrophy have multiple risk factors for lower extremity oedema. This study sought to define the frequency and predictors of oedema. Patients aged 15 years and older were screened by patient questionnaire, and the presence of oedema was confirmed by subsequent physical exam. Twenty-four of 52 patients (46%) had oedema, 12 of whom had swelling extending above the foot and two with sores/skin breakdown. There was no significant difference in age, frequency, or duration of glucocorticoid use, non-invasive respiratory support use, forced vital capacity, cardiac medication use, or ejection fraction between patients with and without oedema (all p > 0.2). Those with oedema had a greater time since the loss of ambulation (8.4 years versus 3.5 years; p = 0.004), higher body mass index (28.3 versus 24.8; p = 0.014), and lower frequency of deflazacort use (67% versus 89%; p = 0.008). Multivariate analysis revealed a longer duration of loss of ambulation (p = 0.02) and higher body mass index (p = 0.009) as predictors of oedema. Lower extremity oedema is common in Duchenne muscular dystrophy but independent of cardiac function. Interventions focused on minimising body mass index increases over time may be a therapeutic target.
In March 2020, New York City became the epicenter of the coronavirus disease 2019 (COVID-19) pandemic in the United States. Because healthcare facilities were overwhelmed with patients, the Jacob K. Javits Convention Center was transformed into the nation’s largest alternate care site: Javits New York Medical Station (hereafter termed Javits). Protecting healthcare workers (HCWs) during a global shortage of personal protective equipment (PPE) in a nontraditional healthcare setting posed unique challenges. We describe components of the HCW safety program implemented at Javits.
Setting:
Javits, a large convention center transformed into a field hospital, with clinical staff from the US Public Health Service Commissioned Corps and the US Department of Defense.
Methods:
Key strategies to ensure HCW safety included ensuring 1-way flow of traffic on and off the patient floor, developing a matrix detailing PPE required for each work activity and location, PPE extended use and reuse protocols, personnel training, and monitoring adherence to PPE donning/doffing protocols when entering or exiting the patient floor. Javits staff who reported COVID-19 symptoms were immediately isolated, monitored, and offered a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction (RT-PCR) test.
Conclusions:
A well-designed and implemented HCW safety plan can minimize the risk of SARS-CoV-2 infection for HCWs. The lessons learned from operating the nation’s largest COVID-19 alternate care site can be adapted to other environments during public health emergencies.
As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring.
Methods:
The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed.
Results:
Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial’s DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report.
Conclusion:
It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
To date, besides genome-wide association studies, a variety of other genetic analyses (e.g. polygenic risk scores, whole-exome sequencing and whole-genome sequencing) have been conducted, and a large amount of data has been gathered for investigating the involvement of common, rare and very rare types of DNA sequence variants in bipolar disorder. Also, non-invasive neuroimaging methods can be used to quantify changes in brain structure and function in patients with bipolar disorder.
Aims
To provide a comprehensive assessment of genetic findings associated with bipolar disorder, based on the evaluation of different genomic approaches and neuroimaging studies.
Method
We conducted a PubMed search of all relevant literatures from the beginning to the present, by querying related search strings.
Results
ANK3, CACNA1C, SYNE1, ODZ4 and TRANK1 are five genes that have been replicated as key gene candidates in bipolar disorder pathophysiology, through the investigated studies. The percentage of phenotypic variance explained by the identified variants is small (approximately 4.7%). Bipolar disorder polygenic risk scores are associated with other psychiatric phenotypes. The ENIGMA-BD studies show a replicable pattern of lower cortical thickness, altered white matter integrity and smaller subcortical volumes in bipolar disorder.
Conclusions
The low amount of explained phenotypic variance highlights the need for further large-scale investigations, especially among non-European populations, to achieve a more complete understanding of the genetic architecture of bipolar disorder and the missing heritability. Combining neuroimaging data with genetic data in large-scale studies might help researchers acquire a better knowledge of the engaged brain regions in bipolar disorder.
Fibricola and Neodiplostomum are diplostomid genera with very similar morphology that are currently separated based on their definitive hosts. Fibricola spp. are normally found in mammals, while Neodiplostomum spp. typically parasitize birds. Previously, no DNA sequence data was available for any member of Fibricola. We generated nuclear ribosomal and mtDNA sequences of Fibricola cratera (type-species), Fibricola lucidum and 6 species of Neodiplostomum. DNA sequences were used to examine phylogenetic interrelationships among Fibricola and Neodiplostomum and re-evaluate their systematics. Molecular phylogenies and morphological study suggest that Fibricola should be considered a junior synonym of Neodiplostomum. Therefore, we synonymize the two genera and transfer all members of Fibricola into Neodiplostomum. Specimens morphologically identified as Neodiplostomum cratera belonged to 3 distinct phylogenetic clades based on mitochondrial data. One of those clades also included sequences of specimens identified morphologically as Neodiplostomum lucidum. Further study is necessary to resolve the situation regarding the morphology of N. cratera. Our results demonstrated that some DNA sequences of N. americanum available in GenBank originate from misidentified Neodiplostomum banghami. Molecular phylogentic data revealed at least 2 independent host-switching events between avian and mammalian hosts in the evolutionary history of Neodiplostomum; however, the directionality of these host-switching events remains unclear.
Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants (N = 56; Mage = 23.74, range = 18–30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.
Two introduced carnivores, the European red fox Vulpes vulpes and domestic cat Felis catus, have had extensive impacts on Australian biodiversity. In this study, we collate information on consumption of Australian birds by the fox, paralleling a recent study reporting on birds consumed by cats. We found records of consumption by foxes on 128 native bird species (18% of the non-vagrant bird fauna and 25% of those species within the fox’s range), a smaller tally than for cats (343 species, including 297 within the fox’s Australian range, a subset of that of the cat). Most (81%) bird species eaten by foxes are also eaten by cats, suggesting that predation impacts are compounded. As with consumption by cats, birds that nest or forage on the ground are most likely to be consumed by foxes. However, there is also some partitioning, with records of consumption by foxes but not cats for 25 bird species, indicating that impacts of the two predators may also be complementary. Bird species ≥3.4 kg were more likely to be eaten by foxes, and those <3.4 kg by cats. Our compilation provides an inventory and describes characteristics of Australian bird species known to be consumed by foxes, but we acknowledge that records of predation do not imply population-level impacts. Nonetheless, there is sufficient information from other studies to demonstrate that fox predation has significant impacts on the population viability of some Australian birds, especially larger birds, and those that nest or forage on the ground.
To understand the transmission dynamics of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in a hospital outbreak to inform infection control actions.
Design:
Retrospective cohort study.
Setting:
General medical and elderly inpatient wards in a hospital in England.
Methods:
Coronavirus disease 2019 (COVID-19) patients were classified as community or healthcare associated by time from admission to onset or positivity using European Centre for Disease Prevention and Control definitions. COVID-19 symptoms were classified as asymptomatic, nonrespiratory, or respiratory. Infectiousness was calculated from 2 days prior to 14 days after symptom onset or positive test. Cases were defined as healthcare-associated COVID-19 when infection was acquired from the wards under investigation. COVID-19 exposures were calculated based on symptoms and bed proximity to an infectious patient. Risk ratios and adjusted odds ratios (aORs) were calculated from univariable and multivariable logistic regression.
Results:
Of 153 patients, 65 were COVID-19 patients and 45 of these were healthcare-associated cases. Exposure to a COVID-19 patient with respiratory symptoms was associated with healthcare-associated infection irrespective of proximity (aOR, 3.81; 95% CI, 1.6.3–8.87). Nonrespiratory exposure was only significant within 2.5 m (aOR, 5.21; 95% CI, 1.15–23.48). A small increase in risk ratio was observed for exposure to a respiratory patient for >1 day compared to 1 day from 2.04 (95% CI, 0.99–4.22) to 2.36 (95% CI, 1.44–3.88).
Conclusions:
Respiratory exposure anywhere within a 4-bed bay was a risk, whereas nonrespiratory exposure required bed distance ≤2.5 m. Standard infection control measures required beds to be >2 m apart. Our findings suggest that this may be insufficient to stop SARS-CoV-2 transmission. We recommend improving cohorting and further studies into bed distance and transmission factors.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.