| 1. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Zohm, H., et al.
(author)
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Overview of ASDEX upgrade results in view of ITER and DEMO
- 2024
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In: Nuclear Fusion. - 0029-5515 .- 1741-4326. ; 64:11
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Journal article (peer-reviewed)abstract
- Experiments on ASDEX Upgrade (AUG) in 2021 and 2022 have addressed a number of critical issues for ITER and EU DEMO. A major objective of the AUG programme is to shed light on the underlying physics of confinement, stability, and plasma exhaust in order to allow reliable extrapolation of results obtained on present day machines to these reactor-grade devices. Concerning pedestal physics, the mitigation of edge localised modes (ELMs) using resonant magnetic perturbations (RMPs) was found to be consistent with a reduction of the linear peeling-ballooning stability threshold due to the helical deformation of the plasma. Conversely, ELM suppression by RMPs is ascribed to an increased pedestal transport that keeps the plasma away from this boundary. Candidates for this increased transport are locally enhanced turbulence and a locked magnetic island in the pedestal. The enhanced D-alpha (EDA) and quasi-continuous exhaust (QCE) regimes have been established as promising ELM-free scenarios. Here, the pressure gradient at the foot of the H-mode pedestal is reduced by a quasi-coherent mode, consistent with violation of the high-n ballooning mode stability limit there. This is suggestive that the EDA and QCE regimes have a common underlying physics origin. In the area of transport physics, full radius models for both L- and H-modes have been developed. These models predict energy confinement in AUG better than the commonly used global scaling laws, representing a large step towards the goal of predictive capability. A new momentum transport analysis framework has been developed that provides access to the intrinsic torque in the plasma core. In the field of exhaust, the X-Point Radiator (XPR), a cold and dense plasma region on closed flux surfaces close to the X-point, was described by an analytical model that provides an understanding of its formation as well as its stability, i.e., the conditions under which it transitions into a deleterious MARFE with the potential to result in a disruptive termination. With the XPR close to the divertor target, a new detached divertor concept, the compact radiative divertor, was developed. Here, the exhaust power is radiated before reaching the target, allowing close proximity of the X-point to the target. No limitations by the shallow field line angle due to the large flux expansion were observed, and sufficient compression of neutral density was demonstrated. With respect to the pumping of non-recycling impurities, the divertor enrichment was found to mainly depend on the ionisation energy of the impurity under consideration. In the area of MHD physics, analysis of the hot plasma core motion in sawtooth crashes showed good agreement with nonlinear 2-fluid simulations. This indicates that the fast reconnection observed in these events is adequately described including the pressure gradient and the electron inertia in the parallel Ohm’s law. Concerning disruption physics, a shattered pellet injection system was installed in collaboration with the ITER International Organisation. Thanks to the ability to vary the shard size distribution independently of the injection velocity, as well as its impurity admixture, it was possible to tailor the current quench rate, which is an important requirement for future large devices such as ITER. Progress was also made modelling the force reduction of VDEs induced by massive gas injection on AUG. The H-mode density limit was characterised in terms of safe operational space with a newly developed active feedback control method that allowed the stability boundary to be probed several times within a single discharge without inducing a disruptive termination. Regarding integrated operation scenarios, the role of density peaking in the confinement of the ITER baseline scenario (high plasma current) was clarified. The usual energy confinement scaling ITER98(p,y) does not capture this effect, but the more recent H20 scaling does, highlighting again the importance of developing adequate physics based models. Advanced tokamak scenarios, aiming at large non-inductive current fraction due to non-standard profiles of the safety factor in combination with high normalised plasma pressure were studied with a focus on their access conditions. A method to guide the approach of the targeted safety factor profiles was developed, and the conditions for achieving good confinement were clarified. Based on this, two types of advanced scenarios (‘hybrid’ and ‘elevated’ q-profile) were established on AUG and characterised concerning their plasma performance.
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| 3. |
- Mullins, N., et al.
(author)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 4. |
- Barucca, G., et al.
(author)
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Study of excited Ξ baryons with the P¯ ANDA detector
- 2021
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In: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Journal article (peer-reviewed)abstract
- The study of baryon excitation spectra provides insight into the inner structure of baryons. So far, most of the world-wide efforts have been directed towards N∗ and Δ spectroscopy. Nevertheless, the study of the double and triple strange baryon spectrum provides independent information to the N∗ and Δ spectra. The future antiproton experiment P¯ANDA will provide direct access to final states containing a Ξ¯ Ξ pair, for which production cross sections up to μb are expected in p¯p reactions. With a luminosity of L= 10 31 cm- 2 s- 1 in the first phase of the experiment, the expected cross sections correspond to a production rate of ∼106events/day. With a nearly 4 π detector acceptance, P¯ANDA will thus be a hyperon factory. In this study, reactions of the type p¯p → Ξ¯ +Ξ∗ - as well as p¯p → Ξ¯ ∗ +Ξ- with various decay modes are investigated. For the exclusive reconstruction of the signal events a full decay tree fit is used, resulting in reconstruction efficiencies between 3 and 5%. This allows high statistics data to be collected within a few weeks of data taking.
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| 5. |
- Barucca, G., et al.
(author)
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The potential of Λ and Ξ- studies with PANDA at FAIR
- 2021
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In: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 57:4
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Journal article (peer-reviewed)abstract
- The antiproton experiment PANDA at FAIR is designed to bring hadron physics to a new level in terms of scope, precision and accuracy. In this work, its unique capability for studies of hyperons is outlined. We discuss ground-state hyperons as diagnostic tools to study non-perturbative aspects of the strong interaction, and fundamental symmetries. New simulation studies have been carried out for two benchmark hyperon-antihyperon production channels: p¯ p→ Λ¯ Λ and p¯ p→ Ξ¯ +Ξ-. The results, presented in detail in this paper, show that hyperon-antihyperon pairs from these reactions can be exclusively reconstructed with high efficiency and very low background contamination. In addition, the polarisation and spin correlations have been studied, exploiting the weak, self-analysing decay of hyperons and antihyperons. Two independent approaches to the finite efficiency have been applied and evaluated: one standard multidimensional efficiency correction approach, and one efficiency independent approach. The applicability of the latter was thoroughly evaluated for all channels, beam momenta and observables. The standard method yields good results in all cases, and shows that spin observables can be studied with high precision and accuracy already in the first phase of data taking with PANDA.
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| 6. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 7. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 8. |
- Aguilar, J. A., et al.
(author)
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Triboelectric backgrounds to radio-based polar ultra-high energy neutrino (UHEN) experiments
- 2023
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In: Astroparticle physics. - : Elsevier. - 0927-6505 .- 1873-2852. ; 145
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Journal article (peer-reviewed)abstract
- In the hopes of observing the highest-energy neutrinos (E> 1 EeV) populating the Universe, both past (RICE, AURA, ANITA) and current (RNO-G, ARIANNA, ARA and TAROGE-M) polar-sited experiments exploit the impulsive radio emission produced by neutrino interactions. In such experiments, rare single event candidates must be unambiguously identified above backgrounds. Background rejection strategies to date primarily target thermal noise fluctuations and also impulsive radio-frequency signals of anthropogenic origin. In this paper, we consider the possibility that 'fake' neutrino signals may also be generated naturally via the `triboelectric effect' This broadly describes any process in which force applied at a boundary layer results in displacement of surface charge, leading to the production of an electrostatic potential difference AV. Wind blowing over granular surfaces such as snow can induce such a potential difference, with subsequent coronal discharge. Discharges over timescales as short as nanoseconds can then lead to radio-frequency emissions at characteristic MHz-GHz frequencies. Using data from various past (RICE, AURA, SATRA, ANITA) and current (RNO G, ARIANNA and ARA) neutrino experiments, we find evidence for such backgrounds, which are generally characterized by: (a) a threshold wind velocity which likely depends on the experimental trigger criteria and layout; for the experiments considered herein, this value is typically O(10 m/s), (b) frequency spectra generally shifted to the low-end of the frequency regime to which current radio experiments are typically sensitive (100-200 MHz), (c) for the strongest background signals, an apparent preference for discharges from above-surface structures, although the presence of more isotropic, lower amplitude triboelectric discharges cannot be excluded.
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| 10. |
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