| 1. |
- Craddock, Nick, et al.
(författare)
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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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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 3. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 4. |
- Bentley, Michael J., et al.
(författare)
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A community-based geological reconstruction of Antarctic Ice Sheet deglaciation since the Last Glacial Maximum
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 100, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- A robust understanding of Antarctic Ice Sheet deglacial history since the Last Glacial Maximum is important in order to constrain ice sheet and glacial-isostatic adjustment models, and to explore the forcing mechanisms responsible for ice sheet retreat. Such understanding can be derived from a broad range of geological and glaciological datasets and recent decades have seen an upsurge in such data gathering around the continent and Sub-Antarctic islands. Here, we report a new synthesis of those datasets, based on an accompanying series of reviews of the geological data, organised by sector. We present a series of timeslice maps for 20 ka, 15 ka, 10 ka and 5 ka, including grounding line position and ice sheet thickness changes, along with a clear assessment of levels of confidence. The reconstruction shows that the Antarctic Ice sheet did not everywhere reach the continental shelf edge at its maximum, that initial retreat was asynchronous, and that the spatial pattern of deglaciation was highly variable, particularly on the inner shelf. The deglacial reconstruction is consistent with a moderate overall excess ice volume and with a relatively small Antarctic contribution to meltwater pulse la. We discuss key areas of uncertainty both around the continent and by time interval, and we highlight potential priorities for future work. The synthesis is intended to be a resource for the modelling and glacial geological community.
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| 5. |
- Mehrtens, Nicola, et al.
(författare)
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The XMM Cluster Survey : optical analysis methodology and the first data release
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 423:2, s. 1024-1052
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Tidskriftsartikel (refereegranskat)abstract
- The XMM Cluster Survey (XCS) is a serendipitous search for galaxy clusters using all publicly available data in the XMMNewton Science Archive. Its main aims are to measure cosmological parameters and trace the evolution of X-ray scaling relations. In this paper we present the first data release from the XMM Cluster Survey (XCS-DR1). This consists of 503 optically confirmed, serendipitously detected, X-ray clusters. Of these clusters, 256 are new to the literature and 357 are new X-ray discoveries. We present 463 clusters with a redshift estimate (0.06 < z < 1.46), including 261 clusters with spectroscopic redshifts. The remainder have photometric redshifts. In addition, we have measured X-ray temperatures (TX) for 401 clusters (0.4 < TX < 14.7 keV). We highlight seven interesting subsamples of XCS-DR1 clusters: (i) 10 clusters at high redshift (z > 1.0, including a new spectroscopically confirmed cluster at z= 1.01); (ii) 66 clusters with high TX (>5 keV); (iii) 130 clusters/groups with low TX (<2 keV); (iv) 27 clusters with measured TX values in the Sloan Digital Sky Survey (SDSS) Stripe 82 co-add region; (v) 77 clusters with measured TX values in the Dark Energy Survey region; (vi) 40 clusters detected with sufficient counts to permit mass measurements (under the assumption of hydrostatic equilibrium); (vii) 104 clusters that can be used for applications such as the derivation of cosmological parameters and the measurement of cluster scaling relations. The X-ray analysis methodology used to construct and analyse the XCS-DR1 cluster sample has been presented in a companion paper, Lloyd-Davies et al.
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| 6. |
- Ross, Alastair, 1976, et al.
(författare)
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A Whole-Grain-Rich Diet Reduces Urinary Excretion of Markers of Protein Catabolism and Gut Microbiota Metabolism in Healthy Men after One Week
- 2013
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 143:6, s. 766-773
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies consistently find that diets rich in whole-grain (WG) cereals lead to decreased risk of disease compared with refined grain (RG)-based diets. Aside from a greater amount of fiber and micronutrients, possible mechanisms for why WGs may be beneficial for health remain speculative. In an exploratory, randomized, researcher-blinded, crossover trial, we measured metabolic profile differences between healthy participants eating a diet based on WGs compared with a diet based on RGs. Seventeen healthy adult participants (11 female, 6 male) consumed a controlled diet based on either WG-rich or RG-rich foods for 2 wk, followed by the other diet after a 5-wk washout period. Both diets were the same except for the use of WG (150 g/d) or FIG foods. The metabolic profiles of plasma, urine, and fecal water were measured using H-1-nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry (plasma only). After 1 wk of intervention, the WG diet led to decreases in urinary excretion of metabolites related to protein catabolism (urea, methylguanadine), lipid (carnitine and acylcarnitines) and gut microbial (4-hydroxyphenylacetate, trimethylacetate, dimethylacetate) metabolism in men compared with the same time point during the FIG intervention. There were no differences between the interventions after 2 wk. Urinary urea, carnitine, and acylcarnitine were lower at wk 1 of the WG intervention relative to the FIG intervention in all participants. Fecal water short-chain fatty acids acetate and butyrate were relatively greater after the WG diet compared to the RG diet. Although based on a small population and for a short time period, these observations suggest that a WG diet may affect protein metabolism.
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| 7. |
- Stott, John P., et al.
(författare)
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The XMM Cluster Survey : the interplay between the brightest cluster galaxy and the intracluster medium via AGN feedback
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 422:3, s. 2213-2229
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Forskningsöversikt (refereegranskat)abstract
- Using a sample of 123 X-ray clusters and groups drawn from the XMM Cluster Survey first data release, we investigate the interplay between the brightest cluster galaxy (BCG), its black hole and the intracluster/group medium (ICM). It appears that for groups and clusters with a BCG likely to host significant active galactic nuclei (AGN) feedback, gas cooling dominates in those with TX > 2 keV while AGN feedback dominates below. This may be understood through the subunity exponent found in the scaling relation we derive between the BCG mass and cluster mass over the halo mass range 1013 < M500 < 1015 M? and the lack of correlation between radio luminosity and cluster mass, such that BCG AGN in groups can have relatively more energetic influence on the ICM. The LXTX relation for systems with the most massive BCGs, or those with BCGs co-located with the peak of the ICM emission, is steeper than that for those with the least massive and most offset, which instead follows self-similarity. This is evidence that a combination of central gas cooling and powerful, well fuelled AGN causes the departure of the ICM from pure gravitational heating, with the steepened relation crossing self-similarity at TX= 2 keV. Importantly, regardless of their black hole mass, BCGs are more likely to host radio-loud AGN if they are in a massive cluster (TX? 2 keV) and again co-located with an effective fuel supply of dense, cooling gas. This demonstrates that the most massive black holes appear to know more about their host cluster than they do about their host galaxy. The results lead us to propose a physically motivated, empirical definition of cluster and group, delineated at 2 keV.
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| 8. |
- Carlsson, Marcus, et al.
(författare)
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Coronary microembolization causes long-term detrimental effects on regional left ventricular function.
- 2011
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Ingår i: Scandinavian cardiovascular journal : SCJ. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 45, s. 205-214
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objectives. To investigate whether coronary microemboli have long-term effects on left ventricular (LV) function in an experimental model. Furthermore, to determine if first-pass perfusion and late gadolinium enhancement (LGE) patterns differs between small- and large-sized microemboli. Design. Six pigs underwent left anterior descending (LAD)-coronary microembolization with small-sized (40-120 μm, n∼250 000) microemboli using a combined x-ray and MRI-system. MR-images before, one hour after and 7-8 weeks after microembolization were obtained. Results were compared to MRI obtained by large-sized (100-300 μm, n∼7200) microemboli. Results. Cine MRI showed an acute drop in ejection fraction (from 49.5 ± 2.6% to 32.5 ± 2.8) that substantially recovered at 7-8 weeks (47.5 ± 3.2%). Regional LV-function assessed as circumferential, longitudinal and radial strain declined in both microinfarcts and remote regions followed by partial recovery at 7-8 weeks. The decline in LV function and the severe perfusion deficit from the small microemboli was similar to the large microemboli at one hour. There was a significant recovery in perfusion at 7-8 weeks in the microinfarcts. LGE demonstrated the microinfarcts at 7-8 weeks but not at one hour and the microinfarcts were confirmed by histopathology. Conclusion. Microembolization causes long-term, regional LV dysfunction and this study confirmed the need of a comprehensive MRI-protocol for the detection of microinfarcts. These findings suggest that even small microemboli (40-120 μm in diameter), which may escape the distal protective devices influence cardiac function.
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| 9. |
- Hachinski, Vladimir, et al.
(författare)
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Stroke: Working Toward a Prioritized World Agenda
- 2010
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 41:6, s. 1084-1099
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods-Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results-Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. Conclusions-To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
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| 10. |
- Hachinski, Vladimir, et al.
(författare)
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Stroke: Working toward a Prioritized World Agenda
- 2010
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Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 30:2, s. 127-147
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e. g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. Conclusions: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress. Copyright (C) 2010 American Heart Association. Inc., S. Karger AG, Basel, and John Wiley & Sons, Inc.
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