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Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
Dioctophyme renale, the giant kidney worm, is a nematode related to Trichuris sp and is distributed worldwide. These parasites locate in the kidney of their definitive hosts (mainly belonging to the order Carnivora) and have an indirect life cycle with an annelid as the main intermediate host. Humans are rarely affected, but in those that are, 1 or both kidneys are destroyed. In South America, D. renale is widespread in riparian regions where changing climatic conditions, environmental degradation, and compromised sanitation are increasing the risk of distribution of this parasite, including humans. Here, we provide the descriptions of the genetic diversity of the parasite in the region by analysing 73 adult D. renale samples collected from domestic and wild carnivores. The most common hosts were (Canis lupus familiaris) and maned wolf (Chrysocyon brachyurus Fam. Canidae) among domestic and wild carnivores, respectively. This work shows the descriptions of the genetic diversity of this parasite complementing molecular methods and classical and probabilistic phylogeography. Our results strongly suggest that this parasite has been present on the continent long enough to develop local genetic variants. Also, the phylogenies show transmission between localities and bidirectional transmission between domestic and wild species. We now have new tools to understand the ecological dynamics of this parasite such as molecular markers to study its genetic diversity as well as for identification and reporting in cryptic cases.
From early on, infants show a preference for infant-directed speech (IDS) over adult-directed speech (ADS), and exposure to IDS has been correlated with language outcome measures such as vocabulary. The present multi-laboratory study explores this issue by investigating whether there is a link between early preference for IDS and later vocabulary size. Infants’ preference for IDS was tested as part of the ManyBabies 1 project, and follow-up CDI data were collected from a subsample of this dataset at 18 and 24 months. A total of 341 (18 months) and 327 (24 months) infants were tested across 21 laboratories. In neither preregistered analyses with North American and UK English, nor exploratory analyses with a larger sample did we find evidence for a relation between IDS preference and later vocabulary. We discuss implications of this finding in light of recent work suggesting that IDS preference measured in the laboratory has low test-retest reliability.
White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.
Participants and Methods:
240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.
Results:
In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).
Conclusions:
These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.
We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems.
Technical summary
The Intergovernmental Panel on Climate Change Assessment Reports provides the scientific foundation for international climate negotiations and constitutes an unmatched resource for researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding of climate change across diverse research communities, we have streamlined an annual process to identify and synthesize significant research advances. We collected input from experts on various fields using an online questionnaire and prioritized a set of 10 key research insights with high policy relevance. This year, we focus on: (1) the looming overshoot of the 1.5°C warming limit, (2) the urgency of fossil fuel phase-out, (3) challenges to scale-up carbon dioxide removal, (4) uncertainties regarding future natural carbon sinks, (5) the need for joint governance of biodiversity loss and climate change, (6) advances in understanding compound events, (7) accelerated mountain glacier loss, (8) human immobility amidst climate risks, (9) adaptation justice, and (10) just transitions in food systems. We present a succinct account of these insights, reflect on their policy implications, and offer an integrated set of policy-relevant messages. This science synthesis and science communication effort is also the basis for a policy report contributing to elevate climate science every year in time for the United Nations Climate Change Conference.
Social media summary
We highlight recent and policy-relevant advances in climate change research – with input from more than 200 experts.
Online, social media communication is often ambiguous, and it can encourage speed and inattentiveness. We investigated whether Actively Open Minded Thinking (AOT), a dispositional willingness to seek out new or potentially threatening information, may help users avoid these pitfalls. In Study 1, we determined that correctly assessing social media authors’ traits was positively predicted by raters’ AOT. In Study 2, we used data-driven methods to devise a three-dimensional picture of online behaviors of people high or low in AOT, finding that AOT is associated with thoughtful, nuanced, idiosyncratic actions and with resisting the typically fast pace of online interactions. AOT may be an important factor in accurate, socially responsible online behavior.
This volume of the Haskins Society Journal brings together a rich and interdisciplinary collection of articles. Topics range from the politics and military organization of northern worlds of the Anglo-Normans and Angevins in the twelfth and thirteenth centuries, to the economic activity of women in Catalonia and political unrest in thirteenth-century Tripoli. Martin Millett's chapter on thesignificance of rural life in Roman Britain for the early Middle Ages continues the Journal's commitment to archaeological approaches to medieval history, while contributions on �lfric's complex use of sources in his homilies, Byrhtferth of Ramsey's reinterpretation of the Alfredian past, and the little known History of Alfred of Beverly engage with crucial questions of sources andhistoriographical production within Anglo-Saxon and Anglo-Norman England. Pieces on the political meaning of the Empress Helena and Constantine I for Angevin political ambitions and the role of relicssuch as the Holy Lance in strategies of political legitimation in Anglo-Saxon England and Ottonian Germany in the tenth century complete the volume.
Contributors: David Bachrach, Mark Blincoe, Katherine Cross, Sarah Ifft Decker, Joyce Hill, Katherine Hodges-Kluck, Jesse Izzo, Martin Millett, John Patrick Slevin, Oliver Stoutner, Laura Wangerin.
Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.
Methods
Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.
Results
Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.
Conclusions
Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Mars exploration motivates the search for extraterrestrial life, the development of space technologies, and the design of human missions and habitations. Here, we seek new insights and pose unresolved questions relating to the natural history of Mars, habitability, robotic and human exploration, planetary protection, and the impacts on human society. Key observations and findings include:
– high escape rates of early Mars' atmosphere, including loss of water, impact present-day habitability;
– putative fossils on Mars will likely be ambiguous biomarkers for life;
– microbial contamination resulting from human habitation is unavoidable; and
– based on Mars' current planetary protection category, robotic payload(s) should characterize the local martian environment for any life-forms prior to human habitation.
Some of the outstanding questions are:
– which interpretation of the hemispheric dichotomy of the planet is correct;
– to what degree did deep-penetrating faults transport subsurface liquids to Mars' surface;
– in what abundance are carbonates formed by atmospheric processes;
– what properties of martian meteorites could be used to constrain their source locations;
– the origin(s) of organic macromolecules;
– was/is Mars inhabited;
– how can missions designed to uncover microbial activity in the subsurface eliminate potential false positives caused by microbial contaminants from Earth;
– how can we ensure that humans and microbes form a stable and benign biosphere; and
– should humans relate to putative extraterrestrial life from a biocentric viewpoint (preservation of all biology), or anthropocentric viewpoint of expanding habitation of space?
Studies of Mars' evolution can shed light on the habitability of extrasolar planets. In addition, Mars exploration can drive future policy developments and confirm (or put into question) the feasibility and/or extent of human habitability of space.
A paleontological deposit near San Clemente de Térapa represents one of the very few Rancholabrean North American Land Mammal Age sites within Sonora, Mexico. During that time, grasslands were common, and the climate included cooler and drier summers and wetter winters than currently experienced in northern Mexico. Here, we demonstrate restructuring in the mammalian community associated with environmental change over the past 40,000 years at Térapa. The fossil community has a similar number of carnivores and herbivores whereas the modern community consists mostly of carnivores. There was also a 97% decrease in mean body size (from 289 kg to 9 kg) because of the loss of megafauna. We further provide an updated review of ungulates and carnivores, recognizing two distinct morphotypes of Equus, including E. scotti and a slighter species; as well as Platygonus compressus; Camelops hesternus; Canis dirus; and Lynx rufus; and the first regional records of Palaeolama mirifica, Procyon lotor, and Smilodon cf. S. fatalis. The Térapa mammals presented here provide a more comprehensive understanding of the faunal community restructuring that occurred in northern Mexico from the late Pleistocene to present day, indicating further potential biodiversity loss with continued warming and drying of the region.
Optimism is associated with reduced cardiovascular disease risk; however, few prospective studies have considered optimism in relation to hypertension risk specifically. We investigated whether optimism was associated with a lower risk of developing hypertension in U.S. service members, who are more likely to develop high blood pressure early in life. We also evaluated race/ethnicity, sex and age as potential effect modifiers of these associations.
Methods
Participants were 103 486 hypertension-free U.S. Army active-duty soldiers (mean age 28.96 years, 61.76% White, 20.04% Black, 11.01% Hispanic, 4.09% Asian, and 3.10% others). We assessed optimism, sociodemographic characteristics, health conditions, health behaviours and depression status at baseline (2009–2010) via self-report and administrative records, and ascertained incident hypertension over follow-up (2010–2014) from electronic health records and health assessments. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and adjusted models for a broad range of relevant covariates.
Results
Over a mean follow-up of 3.51 years, 15 052 incident hypertension cases occurred. The highest v. lowest optimism levels were associated with a 22% reduced risk of developing hypertension, after adjusting for all covariates including baseline blood pressure (HR = 0.78; 95% CI = 0.74–0.83). The difference in hypertension risk between the highest v. lowest optimism was also maintained when we excluded soldiers with hypertension in the first two years of follow-up and, separately, when we excluded soldiers with prehypertension at baseline. A dose–response relationship was evident with higher optimism associated with a lower relative risk (p < 0.001). Higher optimism was consistently associated with a lower risk of developing hypertension across sex, age and most race/ethnicity categories.
Conclusions
In a diverse cohort of initially healthy male and female service members particularly vulnerable to developing hypertension, higher optimism levels were associated with reduced hypertension risk independently of sociodemographic and health factors, a particularly notable finding given the young and healthy population. Results suggest optimism is a health asset and a potential target for public health interventions.
We present a detailed overview of the cosmological surveys that we aim to carry out with Phase 1 of the Square Kilometre Array (SKA1) and the science that they will enable. We highlight three main surveys: a medium-deep continuum weak lensing and low-redshift spectroscopic HI galaxy survey over 5 000 deg2; a wide and deep continuum galaxy and HI intensity mapping (IM) survey over 20 000 deg2 from $z = 0.35$ to 3; and a deep, high-redshift HI IM survey over 100 deg2 from $z = 3$ to 6. Taken together, these surveys will achieve an array of important scientific goals: measuring the equation of state of dark energy out to $z \sim 3$ with percent-level precision measurements of the cosmic expansion rate; constraining possible deviations from General Relativity on cosmological scales by measuring the growth rate of structure through multiple independent methods; mapping the structure of the Universe on the largest accessible scales, thus constraining fundamental properties such as isotropy, homogeneity, and non-Gaussianity; and measuring the HI density and bias out to $z = 6$. These surveys will also provide highly complementary clustering and weak lensing measurements that have independent systematic uncertainties to those of optical and near-infrared (NIR) surveys like Euclid, LSST, and WFIRST leading to a multitude of synergies that can improve constraints significantly beyond what optical or radio surveys can achieve on their own. This document, the 2018 Red Book, provides reference technical specifications, cosmological parameter forecasts, and an overview of relevant systematic effects for the three key surveys and will be regularly updated by the Cosmology Science Working Group in the run up to start of operations and the Key Science Programme of SKA1.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
Methods
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
Results
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
Conclusions
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
The addition of Cr2O3 to modern UO2 fuel modifies the microstructure so that, through the generation of larger grains during fission, a higher proportion of fission gases can be accommodated. This reduces the pellet-cladding mechanical interaction of the fuel rods, allowing the fuels to be “burned” for longer than traditional UO2 fuel, thus maximising the energy obtained. We here describe the preparation of UO2 and Cr-doped UO2 using Hot Isostatic Pressing (HIP), as a potential method for fuel fabrication, and for development of analogue materials for spent nuclear fuel research. Characterization of the synthesised materials confirmed that high density UO2 was successfully formed, and that Cr was present as particles at grain boundaries and also within the UO2 matrix, possibly in a reduced form due to the processing conditions. In contrast to studies of Cr-doped UO2 synthesised by other methods, no significant changes to the grain size were observed in the presence of Cr.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Satellite altimetric time series allow high-precision monitoring of ice-sheet mass balance. Understanding elevation changes in these regions is important because outlet glaciers along ice-sheet margins are critical in controlling flow of inland ice. Here we discuss a new airborne altimetry dataset collected as part of the ICECAP (International Collaborative Exploration of the Cryosphere by Airborne Profiling) project over East Antarctica. Using the ALAMO (Airborne Laser Altimeter with Mapping Optics) system of a scanning photon-counting lidar combined with a laser altimeter, we extend the 2003–09 surface elevation record of NASA’s ICESat satellite, by determining cross-track slope and thus independently correcting for ICESat’s cross-track pointing errors. In areas of high slope, cross-track errors result in measured elevation change that combines surface slope and the actual Δz/Δt signal. Slope corrections are particularly important in coastal ice streams, which often exhibit both rapidly changing elevations and high surface slopes. As a test case (assuming that surface slopes do not change significantly) we observe a lack of ice dynamic change at Cook Ice Shelf, while significant thinning occurred at Totten and Denman Glaciers during 2003–09.
One of the highest priority invasive species at both Yosemite and Sequoia and Kings Canyon national parks is Holcus lanatus L. (common velvetgrass), a perennial bunchgrass that invades mid-elevation montane meadows. Despite velvetgrass being a high priority species, there is little information available on control techniques. The goal of this project was to evaluate the short-term response of a single application of common chemical and manual velvetgrass control techniques. The study was conducted at three montane sites in Yosemite National Park. Glyphosate spot-spray treatments were applied at 0.5, 1.0, 1.5, and 2.0% concentrations, and compared with hand pulling to evaluate effects on cover of common velvetgrass, cover of other plant species, and community species richness. Posttreatment year 1 cover of common velvetgrass was 12.1% ± 1.6 in control plots, 6.3% ± 1.5 averaged over the four chemical treatments (all chemical treatments performed similarly), and 13.6% ± 1.7 for handpulled plots. This represents an approximately 50% reduction in common velvetgrass cover in chemically- treated plots recoded posttreatment year 1 and no statistically significant reduction in hand pulled plots compared with controls. However, there was no treatment effect in posttreatment year 2, and all herbicide application rates performed similarly. In addition, there were no significant treatment effects on nontarget species or species richness. These results suggest that for this level of infestation and habitat type, (1) one year of hand pulling is not an effective control method and (2) glyphosate provides some level of control in the short-term without impact to nontarget plant species, but the effect is temporary as a single year of glyphosate treatment is ineffective over a two-year period.