Genetic risk factors for neurodegenerative diseases and their role in the regulation of regional gene expression in the

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Some of the most common and devastating neurological conditions, including Parkinson‘s and Alzheimer‘s disease, are caused by specific nerve cells in the brain gradually dying. At the moment little is known about why this happens and we cannot stop the process.

Recently neuroscientists have been able to show that some individuals inherit risk factors in their DNA, which make them more likely to develop these neurodegenerative conditions. However, we do not know how these risk factors change the way nerve cells behave or make these cells more vulnerable.

The aim of our work is to investigate how inherited risk factors influence gene expression so that we can understand what types of nerve cell functions change and why the cells die. In order to do this we will use new microarray technologies to obtain detailed genetic and gene expression information about human brain tissue. By understanding how inherited risk factors influence gene expression we hope we can find treatments capable of protecting nerve cells within the brain and so halt the progression of neurodegenerative diseases like Parkinson‘s and Alzheimer‘s disease.

Technical Summary

Neurodegenerative diseases, such as Parkinson‘s and Alzheimer‘s disease, are amongst the most common and devastating neurological conditions. Using whole genome SNP arrays amazing progress has been made in our understanding of the genetic risk factors contributing to the sporadic forms of these conditions. However, since the vast majority of reported risk-associated SNPs are not within coding regions, the identification of these genetic risk factors has not automatically led to a clear understanding of the underlying pathophysiology of neurodegenerative disease.

The biological aim of this study is to fill this gap in our knowledge by identifying SNPs that not only increase an individual‘s risk of developing a neurodegenerative disease, but also change gene expression in the human brain. In support of this research approach, Myers and colleagues demonstrated that high quality gene expression data can be generated from post-mortem brain tissue and that SNP genotypes can be correlated to gene expression levels. Thus, by developing a deeper understanding of the heritability of gene expression within the human brain it should be possible to link genetic risk factors with genes and signalling systems, and so begin to generate new much-needed treatment strategies.

Since risk-associated SNPs are present in the normal population as well as the disease population, using control brain tissue we can study their downstream affects on gene expression without the complications of neuronal death, glial response and symptomatic treatments. We intend to use post-mortem control human brain tissue to collect samples from well-defined brain regions, known to be particularly affected in the most common neurodegenerative diseases. Examples include, the substantia nigra, the site of predominant dopaminergic neuron loss in Parkinson‘s disease.

Using microarray technology, we will rapidly produce large quantities of high quality, genome-wide paired SNP and exon-specific expression data. This information will be stored in a publicly accessible database that can be queried by brain region, SNP or gene transcript. In this way, we hope to generate a resource that will not only be useful for our own research into neurodegenerative diseases, but for those studying other neurological conditions. In our case, the data analysis will be focused on identifying downstream gene expression changes associated with individual SNPs known to increase the risk of developing a neurodegenerative disease.

Thus, we hope to bridge the gap between genetic risk and pathophysiology. In this way, we may be able to provide new therapeutic strategies for the early and effective treatment of neurodegenerative diseases.

Publications

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Salpietro V (2017) The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders. in Brain : a journal of neurology

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Scharf JM (2013) Genome-wide association study of Tourette's syndrome. in Molecular psychiatry

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Stewart SE (2013) Genome-wide association study of obsessive-compulsive disorder. in Molecular psychiatry

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Tucci A (2014) Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. in Journal of neurology, neurosurgery, and psychiatry

 
Description Attachment with Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Invited to attend a workshop on skills development for the NIHR
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Joint Lead for Bioinformatics in Neurology GeCIP
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Project Grant
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2010 
End 03/2013
 
Description Wellcome Biomedical Resource Grant
Amount £200,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 10/2019
 
Title A web-based tool for quality control of eQTL data 
Description This is a web-based tool to allow users to check whether reported eQTLs may be due to systematic errors arising from the presence of polymorphisms within expression microarray probes. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact This is currently being used by our collaborators based in the NIH, but will soon be made publicly available. It has resulted in the identification of a significant number of false positive results. 
 
Title A web-based tool for eQTL analysis and expression profiles 
Description We have created a web-based tool to allow researchers to access the eQTL data we have generated and expression profiles in human brain. 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact This is presently being used by groups within KCL and UCL to follow up GWAS results. 
 
Title Database on genetic variation in neurologically normal individuals over the age of 60 years old 
Description I contributed to the HEXdatabase which provides information on genetic variation in individuals with no evidence of a neurological disorder. 
Type Of Material Biological samples 
Year Produced 2016 
Provided To Others? Yes  
Impact This tool will be released on the Alzform website. 
 
Title Genome-wide gene expression in 10 human brain regions 
Description This is a database of exon-specific gene expression generated from over 800 RNA samples extracted from post-mortem human brain tissue. 
Type Of Material Biological samples 
Provided To Others? No  
Impact This collection of data when released will provide researchers working in the field of neuroscience comprehensive imformation on the expression of all genes within multiple human brain regions. 
 
Description Age-related changes in gene expression in human brain 
Organisation Wellcome Trust
Department Multiple Tissue Human Expression Resource (MuTHER) consortium
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided gene expression data on human brain.
Collaborator Contribution They have provided gene expression data relating to multiple other human tissues.
Impact There is a paper in submission with Genome Research
Start Year 2011
 
Description Collection and analysis of control human post-mortem brain tissue 
Organisation University of Edinburgh
Department Neuropathology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We have supplied our collaborators with information regarding the degree of RNA preservation within banked control human brain tissue.
Collaborator Contribution This collaboration has allowed to collect high quality control human brain tissue for analysis.
Impact This collaboration has allowed us to build a database of exon-specific gene expression in multiple human brain regions.
Start Year 2009
 
Description Genetic risk variants for mesio-temporal lobe epilepsy 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided regional eQTL data and total RNA extracted from human brain tissue originating from neurologically normal individuals.
Collaborator Contribution They have identified risk SNPs for mesio-temporal lobe epilepsy.
Impact There is presently a paper in submission with Nature Genetics.
Start Year 2011
 
Description PARK7 gene structure and expression 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution Expression and RNAseq data and data interpretation relating to PARK7 expression in human brain
Collaborator Contribution Expertise regarding the structure and function of PARK7
Impact Manuscript in preparation
Start Year 2012
 
Description Whole genome expression analysis for the assessment of hESC-derived neuronal maturation 
Organisation University of Edinburgh
Department Centre for Clinical Brain Sciences (CCBS)
Country United Kingdom 
Sector Academic/University 
PI Contribution I have performed the expression and splicing analysis of these samples.
Collaborator Contribution They have provided samples of hESCs, neural precursors and hESc-derived neurons. They have also provided expertise on the process of neural differentiation.
Impact We currently have a paper in submission to Human Molecular Genetics. This collaboration is multidisciplinary with specialist cell and developmental biologists.
Start Year 2011
 
Description Whole genome expression in iPS-derived neurons in health and disease 
Organisation University of Edinburgh
Department MRC Centre for Regenerative Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have performed the analysis of geen expression and splicing in these samples.
Collaborator Contribution It has resulted in the provision of unique samples for the investigation of the impact of specific genetic mutations known to cause Parkinson's Disease on gene expression.
Impact This collaboration has resulted in a publication in Nature Communications and also prompted the submission of a successful project grant to the Alzheimer's Research Trust (£30,000). This is a project using the skills and knowledge of specialist cell biologists with my own technical skills in expression analysis.
Start Year 2011
 
Description eQTL analysis in control human cerebellum and frontal cortex 
Organisation National Center for Biotechnology Information (NCBI)
Country United States 
Sector Public 
PI Contribution We have provided a considerable amount of processed gene expression data.
Collaborator Contribution This collaboration has allowed us to increase the power of our study by increasing the n number and has provided us with technical expertise regarding the analysis of eQTL data.
Impact We have a publication in submission as a direct result of this study.
Start Year 2010
 
Description eQTLs with relevance to brain anatomy as measured by MRI 
Organisation National Center for Biotechnology Information (NCBI)
Country United States 
Sector Public 
PI Contribution We have provided region-specific eQTL data.
Collaborator Contribution The ENIGMA consortium have used MRI scanning and SNP genotyping to identify SNPs that relate to hippocampal volume among other measurements.
Impact This collaboration has resulted in the publication of a Nature Genetics paper.
Start Year 2011
 
Description Neurodegenerative Diseases Initiative Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact This was a day workshop attended by approximately 100 people involved in research on neurodgenerative diseases and interested patient groups. It involved some presentations, but also more informal group discussions.

We have provided additional information regarding our research to a patient group.
Year(s) Of Engagement Activity 2010
 
Description Student visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact An A level studnet visited the lab for one week to observe the research going on in the department.

Since she enjoyed the experience it is likely that other students from her school may well come for visits too.
Year(s) Of Engagement Activity 2011
 
Description Visit from the Michael J Fox Foundation 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This involved presenting our work on LRRK2, implicated in Parkinson's disease to a panel of experts from the Michael J Fox Foundation.

This has resulted in continued contact with the foundation and the funding of a project grant.
Year(s) Of Engagement Activity 2011
 
Description Website - Alzforum 
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 Public/other audiences
Results and Impact Interview has sparked online comments

Requests for data sharing
Year(s) Of Engagement Activity 2014
 
Description Website - SAFARI 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The report has sparked interest in our data set and resources

I have been e-mailed for specific data
Year(s) Of Engagement Activity 2014
 
Description Website -iPSCs 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact A press release was provided to the BBC regarding the results of our study on iPS-derived neurons and this was published on the BBC website.

This resulted in comments from the public and questions from patients in clinics.
Year(s) Of Engagement Activity 2011