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1.
  • Pattaro, Cristian, et al. (författare)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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2.
  • Roselli, Carolina, et al. (författare)
  • Multi-ethnic genome-wide association study for atrial fibrillation
  • 2018
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
  • Tidskriftsartikel (refereegranskat)abstract
    • Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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4.
  • Voight, Benjamin F., et al. (författare)
  • Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
  • 2012
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 380:9841, s. 572-580
  • Tidskriftsartikel (refereegranskat)abstract
    • Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2.6% frequency) had higher HDL cholesterol (0.14 mmol/L higher, p=8x10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0.87, 95% CI 0.84-0.91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0.99, 95% CI 0.88-1.11, p=0.85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0.62, 95% CI 0.58-0.66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0.93, 95% CI 0.68-1.26, p=0.63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1.54, 95% CI 1.45-1.63) was concordant with that from genetic score (OR 2.13, 95% CI 1.69-2.69, p=2x10(-10)). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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5.
  • Wild, Philipp S., et al. (författare)
  • Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
  • 2017
  • Ingår i: Journal of Clinical Investigation. - : Am Soc Clin Investig. - 0021-9738 .- 1558-8238. ; 127:5, s. 1798-1812
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
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6.
  • Aad, G., et al. (författare)
  • Measurement of t(t)over-bar production with a veto on additional central jet activity in pp collisions at root s=7 TeV using the ATLAS detector
  • 2012
  • Ingår i: European Physical Journal C. Particles and Fields. - : Springer. - 1434-6044 .- 1434-6052. ; 72:6
  • Tidskriftsartikel (refereegranskat)abstract
    • A measurement of the jet activity in t (t) over bar events produced in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented, using 2.05 fb(-1) of integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. The t (t) over bar events are selected in the dilepton decay channel with two identified b-jets from the top quark decays. Events are vetoed if they contain an additional jet with transverse momentum above a threshold in a central rapidity interval. The fraction of events surviving the jet veto is presented as a function of this threshold for four different central rapidity interval definitions. An alternate measurement is also performed, in which events are vetoed if the scalar transverse momentum sum of the additional jets in each rapidity interval is above a threshold. In both measurements, the data are corrected for detector effects and compared to the theoretical models implemented in MC@NLO, POWHEG, ALPGEN and SHERPA. The experimental uncertainties are often smaller than the spread of theoretical predictions, allowing deviations between data and theory to be observed in some regions of phase space.
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7.
  • Aad, G., et al. (författare)
  • Measurement of tau polarization in W -> tau nu decays with the ATLAS detector in pp collisions at root s=7 TeV
  • 2012
  • Ingår i: European Physical Journal C. Particles and Fields. - : Springer. - 1434-6044 .- 1434-6052. ; 72:7
  • Tidskriftsartikel (refereegranskat)abstract
    • In this paper, a measurement of tau polarization in W -> tau nu decays is presented. It is measured from the energies of the decay products in hadronic tau decays with a single final state charged particle. The data, corresponding to an integrated luminosity of 24 pb(-1), were collected by the ATLAS experiment at the Large Hadron Collider in 2010. The measured value of the tau polarization is P-tau = -1.06 +/- 0.04 (stat)(-0.07)(+0.05) (syst), in agreement with the Standard Model prediction, and is consistent with a physically allowed 95 % CL interval [-1,-0.91]. Measurements of tau polarization have not previously been made at hadron colliders.
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8.
  • Aad, G., et al. (författare)
  • Measurement of the top quark pair cross section with ATLAS in pp collisions at root s=7 TeV using final states with an electron or a muon and a hadronically decaying tau lepton
  • 2012
  • Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier. - 0370-2693 .- 1873-2445. ; 717:1-3, s. 89-108
  • Tidskriftsartikel (refereegranskat)abstract
    • A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb(-1). Events with an isolated electron or muon and a tau lePton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, sigma(t (t) over bar) = 186 +/- 13 (stat.) +/- 20 (syst.) +/- 7 (lumi.) pb, is in good agreement with the Standard Model prediction. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.
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9.
  • Aad, G., et al. (författare)
  • Measurement of the W W cross section in root s=7 TeV pp collisions with the ATLAS detector and limits on anomalous gauge couplings
  • 2012
  • Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier. - 0370-2693 .- 1873-2445. ; 712:4-5, s. 289-308
  • Tidskriftsartikel (refereegranskat)abstract
    • This Letter reports a measurement of the W W production cross section in root s = 7 TeV pp collisions using data corresponding to an integrated luminosity of 1.02 fb(-1) collected with the ATLAS detector. Using leptonic decays of oppositely charged W bosons, the total measured cross section is sigma (pp -> W W) = 54.4 +/- 4.0 (stat.) +/- 3.9 (syst.) +/- 2.0 (lumi.) pb, consistent with the Standard Model prediction of sigma (pp -> W W)= 44.4 +/- 2.8 pb. Limits on anomalous electroweak triple-gauge couplings are extracted from a fit to the transverse-momentum distribution of the leading charged lepton in the event. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.
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10.
  • Aad, G., et al. (författare)
  • Search for charged Higgs bosons decaying via H-+/- -> tau nu in t(t)over-bar events using pp collision data at root s=7 TeV with the ATLAS detector
  • 2012
  • Ingår i: Journal of High Energy Physics. - : Springer. - 1029-8479 .- 1126-6708. ; :6
  • Tidskriftsartikel (refereegranskat)abstract
    • The results of a search for charged Higgs bosons are presented. The analysis is based on 4.6 fb(-1) of proton-proton collision data at root s = 7TeV collected by the ATLAS experiment at the Large Hadron Collider, using top quark pair events with a tau lepton in the final state. The data are consistent with the expected background from Standard Model processes. Assuming that the branching ratio of the charged Higgs boson to a tau lepton and a neutrino is 100%, this leads to upper limits on the branching ratio of top quark decays to a b quark and a charged Higgs boson between 5% and 1% for charged Higgs boson masses ranging from 90GeV to 160GeV, respectively. In the context of the m(h)(max) scenario of the MSSM, tan beta above 12-26, as well as between 1 and 2-6, can be excluded for charged Higgs boson masses between 90GeV and 150GeV.
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