| 1. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 2. |
- Craddock, Nick, et al.
(author)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 3. |
- Speliotes, Elizabeth K., et al.
(author)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)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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| 4. |
- Yang, Jian, et al.
(author)
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FTO genotype is associated with phenotypic variability of body mass index
- 2012
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
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Journal article (peer-reviewed)abstract
- There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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| 5. |
- Abbasi, R., et al.
(author)
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Constraints on high-energy neutrino emission from SN 2008D
- 2011
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 527:4, s. A28-
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Journal article (peer-reviewed)abstract
- SN 2008D, a core collapse supernova at a distance of 27 Mpc, was serendipitously discovered by the Swift satellite through an associated X-ray flash. Core collapse supernovae have been observed in association with long gamma-ray bursts and X-ray flashes and a physical connection is widely assumed. This connection could imply that some core collapse supernovae possess mildly relativistic jets in which high-energy neutrinos are produced through proton-proton collisions. The predicted neutrino spectra would be detectable by Cherenkov neutrino detectors like IceCube. A search for a neutrino signal in temporal and spatial correlation with the observed X-ray flash of SN 2008D was conducted using data taken in 2007-2008 with 22 strings of the IceCube detector. Events were selected based on a boosted decision tree classifier trained with simulated signal and experimental background data. The classifier was optimized to the position and a "soft jet" neutrino spectrum assumed for SN 2008D. Using three search windows placed around the X-ray peak, emission time scales from 100-10 000 s were probed. No events passing the cuts were observed in agreement with the signal expectation of 0.13 events. Upper limits on the muon neutrino flux from core collapse supernovae were derived for different emission time scales and the principal model parameters were constrained. While no meaningful limits can be given in the case of an isotropic neutrino emission, the parameter space for a jetted emission can be constrained. Future analyses with the full 86 string IceCube detector could detect up to similar to 100 events for a core-collapse supernova at 10 Mpc according to the soft jet model.
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| 6. |
- Abbasi, R., et al.
(author)
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Constraints on the extremely-high energy cosmic neutrino flux with the IceCube 2008-2009 data
- 2011
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In: Physical Review D - Particles, Fields, Gravitation and Cosmology. - 1550-7998 .- 1550-2368. ; 83:9, s. 092003-
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Journal article (peer-reviewed)abstract
- We report on a search for extremely-high energy neutrinos with energies greater than 10(6) GeV using the data taken with the IceCube detector at the South Pole. The data was collected between April 2008 and May 2009 with the half-completed IceCube array. The absence of signal candidate events in the sample of 333.5 days of live time significantly improves model-independent limits from previous searches and allows to place a limit on the diffuse flux of cosmic neutrinos with an E-2 spectrum in the energy range 2.0 x 10(6) - 6.3 x 10(9) GeV to a level of E-2 phi <= 3.6 x 10(-8) GeV cm(-2) sec(-1) sr(-1).
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| 7. |
- Abbasi, R., et al.
(author)
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First search for atmospheric and extraterrestrial neutrino-induced cascades with the IceCube detector
- 2011
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In: Physical Review D. - 1550-7998 .- 1550-2368. ; 84:7, s. 072001-
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Journal article (peer-reviewed)abstract
- We report on the first search for atmospheric and for diffuse astrophysical neutrino-induced showers (cascades) in the IceCube detector using 257 days of data collected in the year 2007-2008 with 22 strings active. A total of 14 events with energies above 16 TeV remained after event selections in the diffuse analysis, with an expected total background contribution of 8.3 +/- 3.6. At 90% confidence we set an upper limit of E(2)Phi(90%CL) < 3.6 x 10(-7) GeV.cm(-2).s(-1).sr(-1) on the diffuse flux of neutrinos of all flavors in the energy range between 24 TeV and 6.6 PeV assuming that Phi proportional to E(-2) and the flavor composition of the nu(e):nu(mu):nu(tau) flux is 1:1:1 at the Earth. The atmospheric neutrino analysis was optimized for lower energies. A total of 12 events were observed with energies above 5 TeV. The observed number of events is consistent with the expected background, within the uncertainties.
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| 8. |
- Abbasi, R., et al.
(author)
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First search for extremely high energy cosmogenic neutrinos with the IceCube Neutrino Observatory
- 2010
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In: Physical review. D, Particles, fields, gravitation, and cosmology. - 1550-7998. ; 82:7, s. 072003-
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Journal article (peer-reviewed)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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| 9. |
- Abbasi, R., et al.
(author)
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Limits on Neutrino Emission from Gamma-Ray Bursts with the 40 String IceCube Detector
- 2011
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In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 106:14, s. 141101-
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Journal article (peer-reviewed)abstract
- IceCube has become the first neutrino telescope with a sensitivity below the TeV neutrino flux predicted from gamma-ray bursts if gamma-ray bursts are responsible for the observed cosmic-ray flux above 10(18) eV. Two separate analyses using the half-complete IceCube detector, one a dedicated search for neutrinos from p gamma interactions in the prompt phase of the gamma-ray burst fireball and the other a generic search for any neutrino emission from these sources over a wide range of energies and emission times, produced no evidence for neutrino emission, excluding prevailing models at 90% confidence.
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| 10. |
- Abbasi, R., et al.
(author)
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Measurement of the anisotropy of cosmic-ray arrival directions with icecube
- 2010
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In: The Astrophysical Journal Letters. - 2041-8205. ; 718, s. L194-L198
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Journal article (peer-reviewed)abstract
- We report the first observation of an anisotropy in the arrival direction of cosmic rays with energies in the multi-TeV region in the Southern sky using data from the IceCube detector. Between 2007 June and 2008 March, the partially deployed IceCube detector was operated in a configuration with 1320 digital optical sensors distributed over 22 strings at depths between 1450 and 2450 m inside the Antarctic ice. IceCube is a neutrino detector, but the data are dominated by a large background of cosmic-ray muons. Therefore, the background data are suitable for high-statistics studies of cosmic rays in the southern sky. The data include 4.3 billion muons produced by downward-going cosmic-ray interactions in the atmosphere; these events were reconstructed with a median angular resolution of 3 degrees and a median energy of similar to 20 TeV. Their arrival direction distribution exhibits an anisotropy in right ascension with a first-harmonic amplitude of (6.4 +/- 0.2 stat. +/- 0.8 syst.) x 10(-4).
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