Genetics, Epigenetics and Bioinformatics

Lead Research Organisation: MRC Prion Unit

Abstract

Human molecular genetics|Most of the UK population has been exposed to Bovine Spongiform Encephalopathy (BSE, commonly known as mad cow disease) by eating contaminated food. The germ that causes BSE, called a prion, may infect humans, resulting in a fatal brain illness called variant Creutzfeldt-Jakob disease (vCJD). While there are few patients to date, we do not know how many might be infected with the disease and develop symptoms later. |vCJD has so far only affected one genetic subtype of individual, found in 40% of healthy people in the UK. Whether other genetic types will become affected, and if so whether they will have an illness like vCJD is unknown. It is clear that genes are important in controlling who will get vCJD. To study this we are using modern technologies to measure many hundreds of thousands of different genetic types, and compare these between groups of the healthy population and vCJD patients.|We are also developing and applying methods to extract, combine and make sense of the huge amount of genetic and other information which is generated by scientists working in the field of molecular biology and Prion research around the world.|Bioinformatics|We are developing and applying methods to extract, combine and make sense of the huge amount of data which is generated by scientists working in the field of molecular biology and Prion research around the world. This includes large sets of data generated by us in the Prion Unit, towards furthering our understanding of the underlying principles of Prion disease. We are able to do this through information technology and the use of fast computers, software programs for analysis and access to data via the internet.

Technical Summary

The MRC Prion Unit Human Molecular Genetics of Prion and Related Dementias Programme investigates why some people, but not others, get prion diseases such as Creutzfeldt-Jakob disease (CJD). By comparing genetic differences between people who developed CJD and healthy people we hope to identify genes that influence why particular people are more susceptible to these diseases, and use this information to better estimate public health risks and to develop new tests and treatments. We also know that the fundamental processes involved in CJD, where one of the bodys own proteins becomes misshapen and then forms large clumps of material, are very relevant to other much commoner diseases such as Alzheimers Disease. ||Evidence in support of the involvement of non- PRNP genetic factors comes in part from work with laboratory inbred mouse strains, detailed in this groups section. A small number (~5) of quantitative trait loci (QTL) responsible for determining incubation time following intra-cerebral inoculation with prions have been mapped by the MRC Prion Unit and others using different crossing strategies and prion strains. The integration of unbiased genome-wide strategies in mouse and human prion disease will be an important in the success of both programs. Our discovery research utilises recently available genome-wide genotyping technologies. We have successfully conducted a pilot genome-wide association study with EA-Affymetrix 500K arrays (Mead et al. Lancet Neurology 2009). The necessary molecular genetic, bioinformatic, and statistical genetic expertise for genome-wide association study is either available in the Unit or through collaboration. Over the next few years we expect to develop our discovery genome-wide association research in larger patient cohorts using more advanced genotyping technologies, and focus on developing cellular and animal models to test the genes identified in our discovery research. It has become increasingly apparent that neurodegenerative diseases share fundamental mechanisms involving protein misfolding, including Alzheimers disease and Parkinsons disease. It is likely that genetic modifiers of prion pathogenesis may be of broader relevance to other protein misfolding diseases, and we intend to explore these possibilities.|One of the key goals of bioinfomatics in the Unit is to identity modifier genes, pathways and mechanisms controlling prion pathogenesis. The objective of this aspect of the programme is to use computational and statistical methods for the analysis and integration of these Unit based large-scale experiments (and also externally generated data sets) and their resulting data sets, which are large, inherently noisy and do not produce necessarily clear candidates.

Publications

10 25 50

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Angus-Leppan H (2013) Autoantibodies in sporadic Creutzfeldt-Jakob disease. in JAMA neurology

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Angus-Leppan H (2013) Creutzfeld-Jakob disease--reply. in JAMA neurology

 
Description Committee attendance
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Development of a national strategy to protect the public from the risks of prion disease transmission through surgical instruments and blood/blood product transfusion committees include acdp, nice, cjd resource centre, presentation to food standards agency
 
Description Genotyping of appendices for Health Protection Agency study
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description CHDI research award
Amount £165,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2016 
End 10/2018
 
Description Development of methods to retrospectively analyse fixed appendix tissue from prevalence studies
Amount £551,099 (GBP)
Organisation Department of Health (DH) 
Sector Public
Country United Kingdom
Start 07/2018 
End 09/2020
 
Description NIHR Senior Investigator
Amount £450,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2018 
End 03/2023
 
Description UCL UCLH Comprehensice Biomedical Centre
Amount £100,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2008 
End 04/2016
 
Description UCLH BRU
Amount £1,250,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2012 
End 04/2017
 
Description Wellcome Trust WTCCC (Genome-wide study of human prion disease)
Amount £568,000 (GBP)
Funding ID 084701 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2008 
End 04/2010
 
Description mrc prion disease research fund
Amount £11,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2017 
End 02/2017
 
Description Alzheimer's disease GWAS 
Organisation Medical Research Council (MRC)
Department MRC Centre for Neuropsychiatric Genetics and Genomics
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution of Alzheimer's disease samples to ongoing GWAS in GERAD, IGAP, PERADES and other funded collaborations led by Cardiff University
Collaborator Contribution Alzheimer's disease GWAS
Impact 26490334 26079503 25778476 25533204 24922517 24231519 24162737 23724096 23193196 23150934 23148125 22693153 22445811 22442439 22405046 22027014 22005930 21812096 21460840 21085570
Start Year 2008
 
Description Data integration 
Organisation Brunel University London
Department School of Information Systems, Computing and Mathematics
Country United Kingdom 
Sector Academic/University 
PI Contribution Data integration collaboration in terms of Prion disease
Impact nothing yet
Start Year 2010
 
Description Genetic studies of populations in the Eastern Highlands Province of Papua New Guinea 
Organisation Papua New Guinea Institute of Medical Research
Country Papua New Guinea 
Sector Public 
PI Contribution Genetic studies
Collaborator Contribution Access to samples and local knowledge
Impact 26061765 25726360 22210626 19923577 19214206 19081515 18849290 18849289 16798390 12690204
 
Description Non-prion dementia genetics prinicpally frontotemporal lobar degeneration, but others 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic analyses, sample archiving and distribution
Collaborator Contribution Clinical data and sample from patients with various neurodegenerative diseases
Impact 28229125 27899424 27581216 26362910 26041104 25662776 25638642 25595499 25160042 24943344 24521566 24510641 24442578 24286341 23998997 23904625 23818065 23649896 23434116 23006986 22406228 22366791 21908872 21849340 21387114 21257233 20490813 20045477 19884572 19864668 19679189 19446372 19217189 18648346 18413474 18234697 16969862 27777022 27524508 26490334 26079503 25959826 25778476 25160042 24162737 23724096 23649896 23150934 23148125 22406228 22027014 22005930 21460840 21193246 21085570 20583301 20209083
Start Year 2006
 
Description Statistical Genetics 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Plans to send genome sequencing data for their support in analysis
Collaborator Contribution Genome wide genetic data including exomes, genomes
Impact None yet
Start Year 2010
 
Title Southern Blot technology in C9orf72 
Description A method to accurately detect and size a large genetic mutation which previously was very hard to diagnose 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Will be licensed to a major US diagnostics company 
 
Title The MRC Dementia Gene Panel 
Description A technology to diagnose all known genetic causes of dementia in a one-step cost effective manner using next generation sequencing technology 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Improved diagnostic accuracy in dementia 
URL https://www.ampliseq.com/protected/tmpl/verifiedPanelsDashboard.action?tmplDesignType=COMMUNITY_PANE...
 
Description Centenial and other annual Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Over 100 attendees including MPs, health professionals, patients, national media, TV interview was done with Director

Exclusive interview on Channel 4 news
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
URL http://www.nationalprionclinic.org
 
Description Conference presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Many each year, often platform presentations, most recently invited to talk at PRION2017, and at ABN annual meeting in London 2016

n/a
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017
 
Description Member of CJD Support Network, presentation at Annual Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact AGM and family support meeting, website design, running the organisation
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018,2019,2020
URL https://www.cjdsupport.net/
 
Description National Prion Clinic Open Days 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 6 hours sited at the MRC Prion Unit at UCL. Several meetings in a year to patient groups, usually 50-70 attendees.

Positive feedback from the process
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020
 
Description Press releases about papers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Major publications are accompanied by press releases, for example in 2013 we issued press releases regarding the development of Southern Blotting technology and the MRC Dementia Gene Panel

Often widely disseminated in the press
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013