| 1. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 2. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Mahajan, Anubha, et al.
(författare)
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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
- 2018
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 50:11, s. 1505-
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Tidskriftsartikel (refereegranskat)abstract
- We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%,14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
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| 4. |
- Parmar, Priyanka, et al.
(författare)
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Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 38, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.
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| 5. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 6. |
- Aartsen, M. G., et al.
(författare)
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Atmospheric and astrophysical neutrinos above 1 TeV interacting in IceCube
- 2015
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 91:2, s. 022001-
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Tidskriftsartikel (refereegranskat)abstract
- The IceCube Neutrino Observatory was designed primarily to search for high-energy (TeV-PeV) neutLrinos produced in distant astrophysical objects. A search for. greater than or similar to 100 TeV neutrinos interacting inside the instrumented volume has recently provided evidence for an isotropic flux of such neutrinos. At lower energies, IceCube collects large numbers of neutrinos from the weak decays of mesons in cosmic-ray air showers. Here we present the results of a search for neutrino interactions inside IceCube's instrumented volume between 1 TeV and 1 PeV in 641 days of data taken from 2010-2012, lowering the energy threshold for neutrinos from the southern sky below 10 TeV for the first time, far below the threshold of the previous high-energy analysis. Astrophysical neutrinos remain the dominant component in the southern sky down to a deposited energy of 10 TeV. From these data we derive new constraints on the diffuse astrophysical neutrino spectrum, Phi(v) = 2.06(-0.3)(+0.4) x 10(-18) (E-v = 10(5) GeV)-2.46 +/- 0.12GeV-1 cm(-2) sr(-1) s(-1) for 25 TeV < E-v < 1.4 PeV, as well as the strongest upper limit yet on the flux of neutrinos from charmed-meson decay in the atmosphere, 1.52 times the benchmark theoretical prediction used in previous IceCube results at 90% confidence.
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| 7. |
- Aartsen, M. G., et al.
(författare)
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Development of a general analysis and unfolding scheme and its application to measure the energy spectrum of atmospheric neutrinos with IceCube
- 2015
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 75:3
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Tidskriftsartikel (refereegranskat)abstract
- We present the development and application of a generic analysis scheme for the measurement of neutrino spectra with the IceCube detector. This scheme is based on regularized unfolding, preceded by an event selection which uses a Minimum Redundancy Maximum Relevance algorithm to select the relevant variables and a random forest for the classification of events. The analysis has been developed using IceCube data from the 59-string configuration of the detector. 27,771 neutrino candidates were detected in 346 days of livetime. A rejection of 99.9999 % of the atmospheric muon background is achieved. The energy spectrum of the atmospheric neutrino flux is obtained using the TRUEE unfolding program. The unfolded spectrum of atmospheric muon neutrinos covers an energy range from 100 GeV to 1 PeV. Compared to the previous measurement using the detector in the 40-string configuration, the analysis presented here, extends the upper end of the atmospheric neutrino spectrum by more than a factor of two, reaching an energy region that has not been previously accessed by spectral measurements.
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| 8. |
- Aartsen, M. G., et al.
(författare)
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Multipole analysis of IceCube data to search for dark matter accumulated in the Galactic halo
- 2015
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 75:1
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Tidskriftsartikel (refereegranskat)abstract
- Dark matter which is bound in the Galactic halo might self-annihilate and produce a flux of stable final state particles, e. g. high energy neutrinos. These neutrinos can be detected with IceCube, a cubic-kilometer sized Cherenkov detector. Given IceCube's large field of view, a characteristic anisotropy of the additional neutrino flux is expected. In this paper we describe a multipole method to search for such a large-scale anisotropy in IceCube data. This method uses the expansion coefficients of a multipole expansion of neutrino arrival directions and incorporates signal-specific weights for each expansion coefficient. We apply the technique to a high-purity muon neutrino sample from the Northern Hemisphere. The final result is compatible with the null-hypothesis. As no signal was observed, we present limits on the self-annihilation cross-section averaged over the relative velocity distribution down to 1.9x10(-23) cm(3) s(-1) for a dark matter particle mass of 700-1,000 GeV and direct annihilation into nu(nu) over bar. The resulting exclusion limits come close to exclusion limits from gamma-ray experiments, that focus on the outer Galactic halo, for high dark matter masses of a few TeV and hard annihilation channels.
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| 9. |
- Aartsen, M. G., et al.
(författare)
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Searches for small-scale anisotropies from neutrino point sources with three years of IceCube data
- 2015
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 66, s. 39-52
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Tidskriftsartikel (refereegranskat)abstract
- Recently, IceCube found evidence for a diffuse signal of astrophysical neutrinos in an energy range of similar to 60 TeV to the PeV-scale [1]. The origin of those events, being a key to understanding the origin of cosmic rays, is still an unsolved question. So far, analyses have not succeeded to resolve the diffuse signal into point-like sources. Searches including a maximum-likelihood-ratio test, based on the reconstructed directions and energies of the detected down- and up-going neutrino candidates, were also performed on IceCube data leading to the exclusion of bright point sources. In this paper, we present two methods to search for faint neutrino point sources in three years of IceCube data, taken between 2008 and 2011. The first method is an autocorrelation test, applied separately to the northern and southern sky. The second method is a multipole analysis, which expands the measured data in the northern hemisphere into spherical harmonics and uses the resulting expansion coefficients to separate signal from background. With both methods, the results are consistent with the background expectation with a slightly more sparse spatial distribution, corresponding to an underfluctuation. Depending on the assumed number of sources, the resulting upper limit on the flux per source in the northern hemisphere for an E-2 energy spectrum ranges from similar to 1.5. 10(-8) GeV/cm(2) s(-1), in the case of one assumed source, to similar to 4. 10(-10) GeV/cm(2) s(-1), in the case of 3500 assumed sources.
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| 10. |
- Aartsen, M. G., et al.
(författare)
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The IceProd framework : Distributed data processing for the IceCube neutrino observatory
- 2015
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Ingår i: Journal of Parallel and Distributed Computing. - : Elsevier BV. - 0743-7315 .- 1096-0848. ; 75, s. 198-211
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Tidskriftsartikel (refereegranskat)abstract
- IceCube is a one-gigaton instrument located at the geographic South Pole, designed to detect cosmic neutrinos, identify the particle nature of dark matter, and study high-energy neutrinos themselves. Simulation of the IceCube detector and processing of data require a significant amount of computational resources. This paper presents the first detailed description of IceProd, a lightweight distributed management system designed to meet these requirements. It is driven by a central database in order to manage mass production of simulations and analysis of data produced by the IceCube detector. IceProd runs as a separate layer on top of other middleware and can take advantage of a variety of computing resources, including grids and batch systems such as CREAM, HTCondor, and PBS. This is accomplished by a set of dedicated daemons that process job submission in a coordinated fashion through the use of middleware plugins that serve to abstract the details of job submission and job management from the framework. (C) 2014 Elsevier Inc. All rights reserved.
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