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- Jaworek, T., et al.
(författare)
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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16, s. E1738-E1754
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
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| 4. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10(-8); joint OR 1·19, 1·12-1·26, p=1·30 × 10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10(-19); joint OR 1·37, 1·30-1·45, p=2·79 × 10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10(-7); joint OR 1·17, 1·11-1·23, p=2·29 × 10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10(-8); joint OR 1·24, 1·15-1·33, p=4·52 × 10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10(-8); joint OR 1·17, 1·11-1·23, p=2·92 × 10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 6. |
- Apponi, A., et al.
(författare)
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Heisenberg's uncertainty principle in the PTOLEMY project : A theory update
- 2022
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Ingår i: Physical Review D. - : American Physical Society. - 2470-0010 .- 2470-0029. ; 106:5
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Tidskriftsartikel (refereegranskat)abstract
- We discuss the consequences of the quantum uncertainty on the spectrum of the electron emitted by the beta-processes of a tritium atom bound to a graphene sheet. We analyze quantitatively the issue recently raised by Cheipesh, Cheianov, and Boyarsky [Phys. Rev. D 104, 116004 (2021)], and discuss the relevant timescales and the degrees of freedom that can contribute to the intrinsic spread in the electron energy. We perform careful calculations of the potential between tritium and graphene with different coverages and geometries. With this at hand, we propose possible avenues to mitigate the effect of the quantum uncertainty.
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| 7. |
- Betti, M. G., et al.
(författare)
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A design for an electromagnetic filter for precision energy measurements at the tritium endpoint
- 2019
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Ingår i: Progress in Particle and Nuclear Physics. - : Elsevier BV. - 0146-6410 .- 1873-2224. ; 106, s. 120-131
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Forskningsöversikt (refereegranskat)abstract
- We present a detailed description of the electromagnetic filter for the PTOLEMY project to directly detect the Cosmic Neutrino Background (CNB). Starting with an initial estimate for the orbital magnetic moment, the higher-order drift process of E x B is configured to balance the gradient-B drift motion of the electron in such a way as to guide the trajectory into the standing voltage potential along the mid-plane of the filter. As a function of drift distance along the length of the filter, the filter zooms in with exponentially increasing precision on the transverse velocity component of the electron kinetic energy. This yields a linear dimension for the total filter length that is exceptionally compact compared to previous techniques for electromagnetic filtering. The parallel velocity component of the electron kinetic energy oscillates in an electrostatic harmonic trap as the electron drifts along the length of the filter. An analysis of the phase-space volume conservation validates the expected behavior of the filter from the adiabatic invariance of the orbital magnetic moment and energy conservation following Liouville's theorem for Hamiltonian systems.
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| 8. |
- Betti, M. G., et al.
(författare)
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Neutrino physics with the PTOLEMY project : active neutrino properties and the light sterile case
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP PUBLISHING LTD. - 1475-7516. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- The PTOLEMY project aims to develop a scalable design for a Cosmic Neutrino Background (CNB) detector, the first of its kind and the only one conceived that can look directly at the image of the Universe encoded in neutrino background produced in the first second after the Big Bang. The scope of the work for the next three years is to complete the conceptual design of this detector and to validate with direct measurements that the non-neutrino backgrounds are below the expected cosmological signal. In this paper we discuss in details the theoretical aspects of the experiment and its physics goals. In particular, we mainly address three issues. First we discuss the sensitivity of PTOLEMY to the standard neutrino mass scale. We then study the perspectives of the experiment to detect the CNB via neutrino capture on tritium as a function of the neutrino mass scale and the energy resolution of the apparatus. Finally, we consider an extra sterile neutrino with mass in the eV range, coupled to the active states via oscillations, which has been advocated in view of neutrino oscillation anomalies. This extra state would contribute to the tritium decay spectrum, and its properties, mass and mixing angle, could be studied by analyzing the features in the beta decay electron spectrum.
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| 9. |
- Suri, P., et al.
(författare)
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Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain
- 2018
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for >= 3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5x10(-8). Suggestive (p<5x10(-7)) and genome-wide significant (p<5x10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2x10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p= 5.3x10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p= 4.5x10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4x10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4x10(-19)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).
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| 10. |
- Apponi, A., et al.
(författare)
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Implementation and optimization of the PTOLEMY transverse drift electromagnetic filter
- 2022
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Ingår i: Journal of Instrumentation. - : IOP Publishing Ltd. - 1748-0221 .- 1748-0221. ; 17:5
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Tidskriftsartikel (refereegranskat)abstract
- The PTOLEMY transverse drift filter is a new concept to enable precision analysis of the energy spectrum of electrons near the tritium beta-decay endpoint. This paper details the implementation and optimization methods for successful operation of the filter for electrons with a known pitch angle. We present the first demonstrator that produces the required magnetic field properties with an iron return-flux magnet. Two methods for the setting of filter electrode voltages are detailed. The challenges of low-energy electron transport in cases of low field are discussed, such as the growth of the cyclotron radius with decreasing magnetic field, which puts a ceiling on filter performance relative to fixed filter dimensions. Additionally, low pitch angle trajectories are dominated by motion parallel to the magnetic field lines and introduce non-adiabatic conditions and curvature drift. To minimize these effects and maximize electron acceptance into the filter, we present a three-potential-well design to simultaneously drain the parallel and transverse kinetic energies throughout the length of the filter. These optimizations are shown, in simulation, to achieve low-energy electron transport from a 1 T iron core (or 3 T superconducting) starting field with initial kinetic energy of 18.6 keV drained to < 10 eV (< 1 eV) in about 80 cm. This result for low field operation paves the way for the first demonstrator of the PTOLEMY spectrometer for measurement of electrons near the tritium endpoint to be constructed at the Gran Sasso National Laboratory (LNGS) in Italy.
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