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2. |
- Adrian-Martinez, S., et al.
(författare)
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A first search for coincident gravitational waves and high energy neutrinos using LIGO, Virgo and ANTARES data from 2007
- 2013
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :6
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Tidskriftsartikel (refereegranskat)abstract
- We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.
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3. |
- Evans, P. A., et al.
(författare)
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Swift Follow-up Observations of Candidate Gravitational-wave Transient Events
- 2012
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Ingår i: The Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 203:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the first multi-wavelength follow-up observations of two candidate gravitational-wave (GW) transient events recorded by LIGO and Virgo in their 2009-2010 science run. The events were selected with low latency by the network of GW detectors (within less than 10 minutes) and their candidate sky locations were observed by the Swift observatory (within 12 hr). Image transient detection was used to analyze the collected electromagnetic data, which were found to be consistent with background. Off-line analysis of the GW data alone has also established that the selected GW events show no evidence of an astrophysical origin; one of them is consistent with background and the other one was a test, part of a "blind injection challenge." With this work we demonstrate the feasibility of rapid follow-ups of GW transients and establish the sensitivity improvement joint electromagnetic and GW observations could bring. This is a first step toward an electromagnetic follow-up program in the regime of routine detections with the advanced GW instruments expected within this decade. In that regime, multi-wavelength observations will play a significant role in completing the astrophysical identification of GW sources. We present the methods and results from this first combined analysis and discuss its implications in terms of sensitivity for the present and future instruments.
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4. |
- Aasi, J., et al.
(författare)
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Parameter estimation for compact binary coalescence signals with the first generation gravitational-wave detector network
- 2013
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 88:6
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Tidskriftsartikel (refereegranskat)abstract
- Compact binary systems with neutron stars or black holes are one of the most promising sources for ground-based gravitational-wave detectors. Gravitational radiation encodes rich information about source physics; thus parameter estimation and model selection are crucial analysis steps for any detection candidate events. Detailed models of the anticipated waveforms enable inference on several parameters, such as component masses, spins, sky location and distance, that are essential for new astrophysical studies of these sources. However, accurate measurements of these parameters and discrimination of models describing the underlying physics are complicated by artifacts in the data, uncertainties in the waveform models and in the calibration of the detectors. Here we report such measurements on a selection of simulated signals added either in hardware or software to the data collected by the two LIGO instruments and the Virgo detector during their most recent joint science run, including a "blind injection'' where the signal was not initially revealed to the collaboration. We exemplify the ability to extract information about the source physics on signals that cover the neutron-star and black-hole binary parameter space over the component mass range 1M(circle dot)-25M(circle dot) and the full range of spin parameters. The cases reported in this study provide a snapshot of the status of parameter estimation in preparation for the operation of advanced detectors.
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5. |
- Aasi, J., et al.
(författare)
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Search for gravitational waves from binary black hole inspiral, merger, and ringdown in LIGO-Virgo data from 2009-2010
- 2013
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 87:2
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Tidskriftsartikel (refereegranskat)abstract
- We report a search for gravitational waves from the inspiral, merger and ringdown of binary black holes (BBH) with total mass between 25 and 100 solar masses, in data taken at the LIGO and Virgo observatories between July 7, 2009 and October 20, 2010. The maximum sensitive distance of the detectors over this period for a (20, 20)M-circle dot coalescence was 300 Mpc. No gravitational wave signals were found. We thus report upper limits on the astrophysical coalescence rates of BBH as a function of the component masses for nonspinning components, and also evaluate the dependence of the search sensitivity on component spins aligned with the orbital angular momentum. We find an upper limit at 90% confidence on the coalescence rate of BBH with nonspinning components of mass between 19 and 28M(circle dot) of 3:3 x 10(-7) mergers Mpc(-3) yr(-1).
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6. |
- Aasi, J., et al.
(författare)
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The characterization of Virgo data and its impact on gravitational-wave searches
- 2012
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Ingår i: Classical and Quantum Gravity. - : IOP Publishing. - 1361-6382 .- 0264-9381. ; 29:15
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Tidskriftsartikel (refereegranskat)abstract
- Between 2007 and 2010 Virgo collected data in coincidence with the LIGO and GEO gravitational-wave (GW) detectors. These data have been searched for GWs emitted by cataclysmic phenomena in the universe, by non-axisymmetric rotating neutron stars or from a stochastic background in the frequency band of the detectors. The sensitivity of GW searches is limited by noise produced by the detector or its environment. It is therefore crucial to characterize the various noise sources in a GW detector. This paper reviews the Virgo detector noise sources, noise propagation, and conversion mechanisms which were identified in the three first Virgo observing runs. In many cases, these investigations allowed us to mitigate noise sources in the detector, or to selectively flag noise events and discard them from the data. We present examples from the joint LIGO-GEO-Virgo GW searches to show how well noise transients and narrow spectral lines have been identified and excluded from the Virgo data. We also discuss how detector characterization can improve the astrophysical reach of GW searches.
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7. |
- Aasi, J., et al.
(författare)
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Einstein@Home all-sky search for periodic gravitational waves in LIGO S5 data
- 2013
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 87:4
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents results of an all-sky search for periodic gravitational waves in the frequency range [50, 1190] Hz and with frequency derivative range of similar to[-20, 1.1] x 10(-10) Hz s(-1) for the fifth LIGO science run (S5). The search uses a noncoherent Hough-transform method to combine the information from coherent searches on time scales of about one day. Because these searches are very computationally intensive, they have been carried out with the Einstein@Home volunteer distributed computing project. Postprocessing identifies eight candidate signals; deeper follow-up studies rule them out. Hence, since no gravitational wave signals have been found, we report upper limits on the intrinsic gravitational wave strain amplitude h(0). For example, in the 0.5 Hz-wide band at 152.5 Hz, we can exclude the presence of signals with h(0) greater than 7.6 x 10(-25) at a 90% confidence level. This search is about a factor 3 more sensitive than the previous Einstein@Home search of early S5 LIGO data.
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8. |
- Abadie, J., et al.
(författare)
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Implementation and testing of the first prompt search for gravitational wave transients with electromagnetic counterparts
- 2012
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 539
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Tidskriftsartikel (refereegranskat)abstract
- Aims. A transient astrophysical event observed in both gravitational wave (GW) and electromagnetic (EM) channels would yield rich scientific rewards. A first program initiating EM follow-ups to possible transient GW events has been developed and exercised by the LIGO and Virgo community in association with several partners. In this paper, we describe and evaluate the methods used to promptly identify and localize GW event candidates and to request images of targeted sky locations. Methods. During two observing periods (Dec. 17, 2009 to Jan. 8, 2010 and Sep. 2 to Oct. 20, 2010), a low-latency analysis pipeline was used to identify GW event candidates and to reconstruct maps of possible sky locations. A catalog of nearby galaxies and Milky Way globular clusters was used to select the most promising sky positions to be imaged, and this directional information was delivered to EM observatories with time lags of about thirty minutes. A Monte Carlo simulation has been used to evaluate the low-latency GW pipeline's ability to reconstruct source positions correctly. Results. For signals near the detection threshold, our low-latency algorithms often localized simulated GW burst signals to tens of square degrees, while neutron star/neutron star inspirals and neutron star/black hole inspirals were localized to a few hundred square degrees. Localization precision improves for moderately stronger signals. The correct sky location of signals well above threshold and originating from nearby galaxies may be observed with similar to 50% or better probability with a few pointings of wide-field telescopes.
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9. |
- Acharya, B. S., et al.
(författare)
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Introducing the CTA concept
- 2013
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Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 43, s. 3-18
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. (C) 2013 Elsevier B.V. All rights reserved.
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10. |
- Abadie, J., et al.
(författare)
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Search for Gravitational Waves Associated with Gamma-Ray Bursts during LIGO Science Run 6 and Virgo Science Runs 2 and 3
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X. ; 760:1
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Tidskriftsartikel (refereegranskat)abstract
- We present the results of a search for gravitational waves associated with 154 gamma-ray bursts (GRBs) that were detected by satellite-based gamma-ray experiments in 2009-2010, during the sixth LIGO science run and the second and third Virgo science runs. We perform two distinct searches: a modeled search for coalescences of either two neutron stars or a neutron star and black hole, and a search for generic, unmodeled gravitational-wave bursts. We find no evidence for gravitational-wave counterparts, either with any individual GRB in this sample or with the population as a whole. For all GRBs we place lower bounds on the distance to the progenitor, under the optimistic assumption of a gravitational-wave emission energy of 10(-2) M-circle dot c(2) at 150 Hz, with a median limit of 17 Mpc. For short-hard GRBs we place exclusion distances on binary neutron star and neutron-star-black-hole progenitors, using astrophysically motivated priors on the source parameters, with median values of 16 Mpc and 28 Mpc, respectively. These distance limits, while significantly larger than for a search that is not aided by GRB satellite observations, are not large enough to expect a coincidence with a GRB. However, projecting these exclusions to the sensitivities of Advanced LIGO and Virgo, which should begin operation in 2015, we find that the detection of gravitational waves associated with GRBs will become quite possible.
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11. |
- Abadie, J., et al.
(författare)
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All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run
- 2012
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 85:12
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Tidskriftsartikel (refereegranskat)abstract
- We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration less than or similar to 1 s over the frequency band 64-5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc(3) for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range similar to 5 x 10(-22) Hz(-1/2) to similar to 1 x 10(-20) Hz(-1/2). The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors.
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12. |
- Abadie, J., et al.
(författare)
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First low-latency LIGO plus Virgo search for binary inspirals and their electromagnetic counterparts
- 2012
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 541
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Tidskriftsartikel (refereegranskat)abstract
- Aims. The detection and measurement of gravitational-waves from coalescing neutron-star binary systems is an important science goal for ground-based gravitational-wave detectors. In addition to emitting gravitational-waves at frequencies that span the most sensitive bands of the LIGO and Virgo detectors, these sources are also amongst the most likely to produce an electromagnetic counterpart to the gravitational-wave emission. A joint detection of the gravitational-wave and electromagnetic signals would provide a powerful new probe for astronomy. Methods. During the period between September 19 and October 20, 2010, the first low-latency search for gravitational-waves from binary inspirals in LIGO and Virgo data was conducted. The resulting triggers were sent to electromagnetic observatories for followup. We describe the generation and processing of the low-latency gravitational-wave triggers. The results of the electromagnetic image analysis will be described elsewhere. Results. Over the course of the science run, three gravitational-wave triggers passed all of the low-latency selection cuts. Of these, one was followed up by several of our observational partners. Analysis of the gravitational-wave data leads to an estimated false alarm rate of once every 6.4 days, falling far short of the requirement for a detection based solely on gravitational-wave data.
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13. |
- Abadie, J., et al.
(författare)
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Upper limits on a stochastic gravitational-wave background using LIGO and Virgo interferometers at 600-1000 Hz
- 2012
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 85:12
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Tidskriftsartikel (refereegranskat)abstract
- A stochastic background of gravitational waves is expected to arise from a superposition of many incoherent sources of gravitational waves, of either cosmological or astrophysical origin. This background is a target for the current generation of ground-based detectors. In this article we present the first joint search for a stochastic background using data from the LIGO and Virgo interferometers. In a frequency band of 600-1000 Hz, we obtained a 95% upper limit on the amplitude of Omega(GW)(f) = Omega(3)(f/900 Hz)(3), of Omega(3) < 0.32, assuming a value of the Hubble parameter of h(100) = 0.71. These new limits are a factor of seven better than the previous best in this frequency band.
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14. |
- Abadie, J., et al.
(författare)
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Search for gravitational waves from intermediate mass binary black holes
- 2012
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 85:10
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Tidskriftsartikel (refereegranskat)abstract
- We present the results of a weakly modeled burst search for gravitational waves from mergers of nonspinning intermediate mass black holes in the total mass range 100-450 M-circle dot and with the component mass ratios between 1: and 4:1. The search was conducted on data collected by the LIGO and Virgo detectors between November of 2005 and October of 2007. No plausible signals were observed by the search which constrains the astrophysical rates of the intermediate mass black holes mergers as a function of the component masses. In the most efficiently detected bin centered on 88 + 88 M-circle dot, for nonspinning sources, the rate density upper limit is 0.13 per Mpc(3) per Myr at the 90% confidence level.
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15. |
- Abadie, J., et al.
(författare)
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Search for gravitational waves from low mass compact binary coalescence in LIGO's sixth science run and Virgo's science runs 2 and 3
- 2012
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 85:8
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Tidskriftsartikel (refereegranskat)abstract
- We report on a search for gravitational waves from coalescing compact binaries using LIGO and Virgo observations between July 7, 2009, and October 20, 2010. We searched for signals from binaries with total mass between 2 and 25M(circle dot); this includes binary neutron stars, binary black holes, and binaries consisting of a black hole and neutron star. The detectors were sensitive to systems up to 40 Mpc distant for binary neutron stars, and further for higher mass systems. No gravitational-wave signals were detected. We report upper limits on the rate of compact binary coalescence as a function of total mass, including the results from previous LIGO and Virgo observations. The cumulative 90% confidence rate upper limits of the binary coalescence of binary neutron star, neutron star-black hole, and binary black hole systems are 1.3 x 10(-4), 3.1 x 10(-5), and 6.4 x 10(-6) Mpc(-3) yr(-1), respectively. These upper limits are up to a factor 1.4 lower than previously derived limits. We also report on results from a blind injection challenge.
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16. |
- Abadie, J., et al.
(författare)
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All-sky search for periodic gravitational waves in the full S5 LIGO data
- 2012
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 85:2
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Tidskriftsartikel (refereegranskat)abstract
- We report on an all-sky search for periodic gravitational waves in the frequency band 50-800 Hz and with the frequency time derivative in the range of 0 through -6 x 10(-9) Hz/s. Such a signal could be produced by a nearby spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. After recent improvements in the search program that yielded a 10x increase in computational efficiency, we have searched in two years of data collected during LIGO's fifth science run and have obtained the most sensitive all-sky upper limits on gravitational-wave strain to date. Near 150 Hz our upper limit on worst-case linearly polarized strain amplitude h(0) is 1 x 10(-24), while at the high end of our frequency range we achieve a worst-case upper limit of 3.8 x 10(-24) for all polarizations and sky locations. These results constitute a factor of 2 improvement upon previously published data. A new detection pipeline utilizing a loosely coherent algorithm was able to follow up weaker outliers, increasing the volume of space where signals can be detected by a factor of 10, but has not revealed any gravitational-wave signals. The pipeline has been tested for robustness with respect to deviations from the model of an isolated neutron star, such as caused by a low-mass or long-period binary companion.
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22. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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26. |
- Actis, M., et al.
(författare)
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Design concepts for the Cherenkov Telescope Array CTA : an advanced facility for ground-based high-energy gamma-ray astronomy
- 2011
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Ingår i: Experimental astronomy. - : Springer. - 0922-6435 .- 1572-9508. ; 32:3, s. 193-316
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Tidskriftsartikel (refereegranskat)abstract
- Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
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28. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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29. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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33. |
- Antoniou, A. C., et al.
(författare)
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Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers : Implications for risk prediction
- 2010
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:23, s. 9742-9754
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Tidskriftsartikel (refereegranskat)abstract
- The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
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34. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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- Kobel, M., et al.
(författare)
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p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Journal of Pathology Clinical Research. - : Wiley. - 2056-4538. ; 9:3, s. 208-222
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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