| 1. |
- Bonham, LW, et al.
(författare)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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| 5. |
- Madireddy, L, et al.
(författare)
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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2236-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.
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| 8. |
- 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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| 11. |
- 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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| 12. |
- Corrigan, S., et al.
(författare)
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Managing the risk of change : A new approach
- 2015
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Ingår i: Safety and Reliability of Complex Engineered Systems - Proceedings of the 25th European Safety and Reliability Conference, ESREL 2015. - : Taylor & Francis Group. - 9781138028791 ; , s. 3443-3446
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Konferensbidrag (refereegranskat)abstract
- While there is wide spread acceptance that the capability for ensuring sustainable change within the aviation industry is critical, the evidence from industrial based case-studies on ‘what factors make for successful change’ and how to ‘manage the risk of change’ have been few and far between. Addressing the very real challenges industry has in implementing sustainable change is the key focus of two EU FP7 collaborative projects called MASCA (MAnaging System Change in Aviation) and PROSPERO (Proactive Safety Performance for Aviation). The MASCA project focused on the processes of change and building the capacity of organisations to manage the change process. PROSPERO is developing a methodology for assessing the risk in the change process based upon the ability to evaluate the change process as it goes through its various phases. All of which are being tested and evaluated through a number of parallel case studies. This paper reports on the development of a system change and operational evaluation tool (SCOPE/Structured Enquiry) which emphasises the following themes: understanding the functionality of the operational system, how this can be enhanced by management processes, the inclusiveness of social relations, trust, the transformative role of information and the development of knowledge. The paper also reports on work linking this framework to an overall system risk model in order to manage the risk in the actual change process itself.
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| 13. |
- McDonald, N., et al.
(författare)
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Proactive safety performance for aviation operations
- 2014
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Ingår i: 11th International Conference on Engineering Psychology and Cognitive Ergonomics, EPCE 2014, Held as Part of 16th International Conference on Human-Computer Interaction, HCI International 2014. - Cham : Springer International Publishing. - 9783319075143 ; , s. 351-362
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Konferensbidrag (refereegranskat)abstract
- The EU Vision 2020 sets a goal of reducing the air travel accident rate by 80%. Achieving this vision requires innovation and a different approach. PROSPERO (Proactive Safety Performance for Operations) is an EU FP7 project that will provide an advanced systemic methodology for managing the improvement process to help achieve that goal, as well as delivering a way of measuring progress. The overall objectives of PROSPERO are to; (i) Provide a proactive anticipation of complex system risks; (ii) Ensure more effective management of and enhanced learning from situations where risks cannot be designed out of the operation and (iii) Achieve substantial improvement in the elimination of and recovery from human error. This paper reports on the overall PROSPERO concept and high level system requirements as they emerged from the first research phase that focused on identifying industry needs.
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