| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)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. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 3. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 4. |
- Abbasi, R., et al.
(författare)
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An improved method for measuring muon energy using the truncated mean of dE/dx
- 2013
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 703, s. 190-198
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Tidskriftsartikel (refereegranskat)abstract
- The measurement of muon energy is critical for many analyses in large Cherenkov detectors, particularly those that involve separating extraterrestrial neutrinos from the atmospheric neutrino background. Muon energy has traditionally been determined by measuring the specific energy loss (dE/dx) along the muon's path and relating the dE/dx to the muon energy. Because high-energy muons (Eμ>1TeV) lose energy randomly, the spread in dE/dx values is quite large, leading to a typical energy resolution of 0.29 in log10(Eμ) for a muon observed over a 1 km path length in the IceCube detector. In this paper, we present an improved method that uses a truncated mean and other techniques to determine the muon energy. The muon track is divided into separate segments with individual dE/dx values. The elimination of segments with the highest dE/dx results in an overall dE/dx that is more closely correlated to the muon energy. This method results in an energy resolution of 0.22 in log10(Eμ), which gives a 26% improvement. This technique is applicable to any large water or ice detector and potentially to large scintillator or liquid argon detectors.
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| 5. |
- Abbasi, R., et al.
(författare)
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Cosmic ray composition and energy spectrum from 1-30 PeV using the 40-string configuration of IceTop and IceCube
- 2013
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 42, s. 15-32
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Tidskriftsartikel (refereegranskat)abstract
- The mass composition of high energy cosmic rays depends on their production, acceleration, and propagation. The study of cosmic ray composition can therefore reveal hints of the origin of these particles. At the South Pole, the IceCube Neutrino Observatory is capable of measuring two components of cosmic ray air showers in coincidence: the electromagnetic component at high altitude (2835 m) using the IceTop surface array, and the muonic component above ∼1 TeV using the IceCube array. This unique detector arrangement provides an opportunity for precision measurements of the cosmic ray energy spectrum and composition in the region of the knee and beyond. We present the results of a neural network analysis technique to study the cosmic ray composition and the energy spectrum from 1 PeV to 30 PeV using data recorded using the 40-string/40-station configuration of the IceCube Neutrino Observatory.
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| 6. |
- Abbasi, R., et al.
(författare)
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Lateral distribution of muons in IceCube cosmic ray events
- 2013
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 87:1, s. 012005-
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Tidskriftsartikel (refereegranskat)abstract
- In cosmic ray air showers, the muon lateral separation from the center of the shower is a measure of the transverse momentum that the muon parent acquired in the cosmic ray interaction. IceCube has observed cosmic ray interactions that produce muons laterally separated by up to 400 m from the shower core, a factor of 6 larger distance than previous measurements. These muons originate in high p(T) (> 2 GeV/c) interactions from the incident cosmic ray, or high-energy secondary interactions. The separation distribution shows a transition to a power law at large values, indicating the presence of a hard p(T) component that can be described by perturbative quantum chromodynamics. However, the rates and the zenith angle distributions of these events are not well reproduced with the cosmic ray models tested here, even those that include charm interactions. This discrepancy may be explained by a larger fraction of kaons and charmed particles than is currently incorporated in the simulations. DOI: 10.1103/PhysRevD.87.012005
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| 7. |
- Abbasi, R., et al.
(författare)
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Searches for high-energy neutrino emission in the galaxy with the combined icecube-amanda detector
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 763:1, s. 33-
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Tidskriftsartikel (refereegranskat)abstract
- We report on searches for neutrino sources at energies above 200 GeV in the Northern sky of the Galactic plane, using the data collected by the South Pole neutrino telescope, IceCube, and AMANDA. The Galactic region considered in this work includes the local arm toward the Cygnus region and our closest approach to the Perseus Arm. The searches are based on the data collected between 2007 and 2009. During this time AMANDA was an integrated part of IceCube, which was still under construction and operated with 22 strings (2007-2008) and 40 strings (2008-2009) of optical modules deployed in the ice. By combining the advantages of the larger IceCube detector with the lower energy threshold of the more compact AMANDA detector, we obtain an improved sensitivity at energies below ∼10 TeV with respect to previous searches. The analyses presented here are a scan for point sources within the Galactic plane, a search optimized for multiple and extended sources in the Cygnus region, which might be below the sensitivity of the point source scan, and studies of seven pre-selected neutrino source candidates. For one of them, Cygnus X-3, a time-dependent search for neutrino emission in coincidence with observed radio and X-ray flares has been performed. No evidence of a signal is found, and upper limits are reported for each of the searches. We investigate neutrino spectra proportional to E -2 and E -3 in order to cover the entire range of possible neutrino spectra. The steeply falling E -3 neutrino spectrum can also be used to approximate neutrino energy spectra with energy cutoffs below 50 TeV since these result in a similar energy distribution of events in the detector. For the region of the Galactic plane visible in the Northern sky, the 90% confidence level muon neutrino flux upper limits are in the range E 3 dN/dE ∼ 5.4-19.5 × 10-11 TeV2 cm-2 s-1 for point-like neutrino sources in the energy region [180.0 GeV-20.5 TeV]. These represent the most stringent upper limits for soft-spectra neutrino sources within the Galaxy reported to date.
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| 8. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 9. |
- Abbasi, R., et al.
(författare)
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Calibration and characterization of the IceCube photomultiplier tube
- 2010
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 618:1-3, s. 139-152
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Tidskriftsartikel (refereegranskat)abstract
- Over 5000 PMTs are being deployed at the South Pole to compose the IceCube neutrino observatory. Many are placed deep in the ice to detect Cherenkov light emitted by the products of high-energy neutrino interactions, and others are frozen into tanks on the surface to detect particles from atmospheric cosmic ray showers. IceCube is using the 10-in. diameter R7081-02 made by Hamamatsu Photonics. This paper describes the laboratory characterization and calibration of these PMTs before deployment. PMTs were illuminated with pulses ranging from single photons to saturation level. Parameterizations are given for the single photoelectron charge spectrum and the saturation behavior. Time resolution, late pulses and afterpulses are characterized. Because the PMTs are relatively large, the cathode sensitivity uniformity was measured. The absolute photon detection efficiency was calibrated using Rayleigh-scattered photons from a nitrogen laser. Measured characteristics are discussed in the context of their relevance to IceCube event reconstruction and simulation efforts. (C) 2010 Elsevier B.V. All rights reserved.
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| 10. |
- Abbasi, R., et al.
(författare)
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First search for extremely high energy cosmogenic neutrinos with the IceCube Neutrino Observatory
- 2010
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Ingår i: Physical review. D, Particles, fields, gravitation, and cosmology. - 1550-7998. ; 82:7, s. 072003-
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Tidskriftsartikel (refereegranskat)abstract
- We report on the results of the search for extremely-high energy neutrinos with energies above 10(7) GeV obtained with the partially (similar to 30%) constructed IceCube in 2007. From the absence of signal events in the sample of 242.1 days of effective live time, we derive a 90% C.L. model independent differential upper limit based on the number of signal events per energy decade at E-2 phi(ve+v mu+v tau) similar or equal to 1.4 x 10(-6) GeV cm(-2) sec(-1) sr(-1) for neutrinos in the energy range from 3 x 10(7) to 3 x 10(9) GeV.
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