Neurological Disease Genomics

Lead Research Organisation: University of Oxford

Abstract

The Neurological Disease Genomics group is identifying the genetics underlying complex neurodevelopmental disorders including autism, intellectual disability and bipolar disorder. It has been estimated, both from studies looking at family inheritance and from studies looking at identical twins, that many neurological disorders have a clearly inherited, or genetic, cause. However, despite several large genetic studies, the genes causing these disorders have not yet been identified. One problem in identifying these genes is that the patients suffering from one of these disorders do not all appear to have mutations affecting only one gene, i.e. people suffering from autism do not all have mutations affecting the same gene. Instead, it appears that different mutations within many different genes, possibly hundreds of different genes, are able to cause the same neurological disorder. The Neurological Disease Genomics group applies computational and statistical techniques to try and identify why many different mutations across many different genes can cause the same, or a similar, set of symptoms. Our aim is to identify the common processes in the brain that these genes participate in and that is disrupted in individuals that suffer from each of these disorders. Identifying the neurological processes disrupted in each of these disorders is an important step towards both understanding and diagnosing the disease and towards finding novel treatments and therapeutics.

Technical Summary

The Neurological Disease Genomics group is gaining insights in to complex neurodevelopmental and neuropsychiatric disorders using functional and integrative genomics approaches. With the advent of high throughput and cost effective microarray and sequencing technologies, patient genotypes are becoming readily accessible. However, interpreting this genetic data to identify the disease-causing variations has thus far proved to be difficult. This is particularly true when variants associated with a given disorder are dispersed across multiple genomic loci, which certainly appears to be the case for many neurodevelopmental (e.g. intellectual disability, autism, ADHD) and neuropsychiatric (e.g. schizophrenia, bipolar affective disorder) disorders. We hypothesise that the reason that mutations at these distinct loci give rise to a common set of symptoms is that they harbour functional elements that participate in common biological processes or pathways. Thus, we exploit functional and integrative genomics approaches to detect functional commonality among these disease-associated dispersed loci, thereby simultaneously identifying both the candidate functional elements and the shared functionality that may yield insights into the underlying etiopathology. Identifying and defining functionality is vital to the success of these approaches. In addition to exploiting popular functional annotations (e.g. GO, KEGG, etc.), we exploit the collected and ontologised phenotypes following the determined disruption of genes within the mouse as a valuable functional genomics resource, able to provide unique insights in to human genetic disorders. By integrating multiple sources of genic annotations within functional linkage networks, we are able to identify detailed functional relationships between genes beyond that provided by any single set of annotations. We hypothesise that the variation in symptoms presented within complex human behavioural spectrum disorders may result from variance among the biological processes affected. Thus, we are applying these functional networks in the analyses of spectrum/variable disorders in order to associate variation in the affected biological processes/networks with the variation in patient presentations, and thereby detect patient subgroups. Current disorders studied in the group include autism, intellectual disability, dyslexia, ADHD, bipolar disorder and schizophrenia. We are applying these approaches to various data sources including Next Generation exome sequence data, CNVs and GWAS-defined association intervals. Identifying biologically-meaningful patient subgroups will be fundamental to better diagnosis, to better target of existing treatments and to the development of novel, more specific, therapeutics. Finally, this research group and its approaches towards identifying pathways is now at the heart of a large 52m euro Innovative Medicines Initiative (IMI) StemBANCC project, in which induced pluripotent stem cells (iPSCs) derived from patients will be generated as cellular models for a range of disorders, including autism, Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar, migraine, diabetes and various neuropathies. Webber is the work package leader for the interpretation of the molecular profile data (transcriptomes, metabolomes, proteomes) generated from these iPSC-derived cellular models of disease, employing network and pathway approaches to identify perturbed cellular pathways relevant to these disorders.

Publications

10 25 50
 
Description IM2PACT
Amount € 9,000,000 (EUR)
Funding ID 807015 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 11/2018 
End 10/2023
 
Description MRC Momentum
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2017 
End 05/2020
 
Description Oxford Parkinson's Disease Consortium 2
Amount £250,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2015 
End 03/2020
 
Title New computational method for predicting whether genes are haploinsufficient 
Description The method using multiple functional genomics resources to evaluate whether a gene is likely to be haploinsufficient or not. The method is designed to be less prone to study-bias, i.e. it's better at evaluating genes that are understudied. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Method published in PMID: 26001969 and implemented by people clinically evaluating genetic variants. 
URL https://www.ncbi.nlm.nih.gov/pubmed/26001969
 
Title Phenotype-linkage network 
Description We have developed a novel phenotype-linkage gene network approach (Honti et al, 2014). Succinctly, this approach integrates any type of functional genomics information (gene expression, interactions, literature, etc) to provide an estimation as to how likely a given pair of genes are to influence the same mammalian phenotype. This method has proved superior to other methods in identifying significantly unusual functional biases amongst variants identified in exome studies. 
Type Of Material Data analysis technique 
Year Produced 2014 
Provided To Others? Yes  
Impact This is now the primary functional analyses tool applied to cell profiling data by groups within the IMI StemBANCC project, a 56M euro grant to develop 1500 stem cell models for a range of disorders. 
 
Description AR UK Oxford Drug Discovery Institute 
Organisation Alzheimer's Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I lead the target discovery team for the newly-established Alzheimer's Research Oxford Target Discovery. My group's computational genomics approaches are identifying the candidate gene/protein target leads that are being investigated for the AD-modulating properties.
Collaborator Contribution The many members of the AR UK ODDI are taking these targets we identify through AD drug development.
Impact Multi-disciplinary drug discovery. See members at URL.
Start Year 2015
 
Description BBC TV interview 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The lead author on a paper from my group was interviewed by BBC South East Today.

We received enquiries from interested members of the public.
Year(s) Of Engagement Activity Pre-2006,2013
URL http://www.bbc.co.uk/programmes/b006pfp8
 
Description Deputy Editor, Bang! (Oxford Science Magazine) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Will Brandler (DPhil student in group) is the Deputy Editor, Bang! (Oxford Science Magazine). With roles to commission, edit and manage articles on website. Select articles for print edition. Bang! has a circulation of ~6,000. Promoted from writer and sub-editor.

Increased Bang! circulation
Year(s) Of Engagement Activity 2012
 
Description Interview on BBC Radio Wales 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview discussing how scientists in Wales are at the centre of health research, this interview focused on work aimed at identifying whether people are at risk of developing dementia
Year(s) Of Engagement Activity 2018
URL https://www.bbc.co.uk/programmes/b0b9zrvv
 
Description Mentor for Oxford Pathways Program 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact Volunteering to give 'Academic Taster Sessions' as part of access initiative to encourage
students from disadvantaged backgrounds to apply to Oxford.


Encouraging pupils from disadvantaged backgrounds to apply to Oxford University
Year(s) Of Engagement Activity 2012
 
Description News coverage in NHS news 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Health professionals
Results and Impact Media coverage of publication

Increased awareness amongst UK health professionals
Year(s) Of Engagement Activity 2013
URL http://www.nhs.uk/news/2013/06June/Pages/scientists-identify-gene-pattern-linked-to-autism.aspx
 
Description News coverage in The Independent 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research in the National press

increased public awareness of research
Year(s) Of Engagement Activity 2013
URL http://www.independent.co.uk/life-style/health-and-families/health-news/scientists-find-gene-pattern...
 
Description PD Patient Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Gave talk to Parkinson's UK Patient forum. Long discussions afterwards and have subsequently been invited to present at a PD UK patient conference in Southampton in June.
Year(s) Of Engagement Activity 2015
 
Description PD UK patient forum talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I gave a PD UK patient forum talk at Waterlooville Community Centre, 10 Maurepas Way, Waterlooville, Hampshire, PO7 7AY. Wed 12/07/2017
"How can skin cells help us find therapeutics for Parkinson's?"
Year(s) Of Engagement Activity 2017
URL https://www.parkinsons.org.uk/
 
Description Parkinson's UK Research Roadshow Cardiff 
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 Public/other audiences
Results and Impact Cardiff edition of Parkinson's UK Research Roadshow took place at Hadyn Ellis Building. It was a UK wide event, inviting patients and family members to hear about exciting research taking place at specific locations and providing information on how involvement in research could help move towards better treatments and ultimately a cure. Interactive discussions with patients, carers and charity workers about 'Can stem cells find new treatments for Parkinson's'
Year(s) Of Engagement Activity 2018
URL https://www.healthandcareresearch.gov.wales/noticeboard/parkinsons-uk-research-roadshow-cardiff/?for...
 
Description Presentation to Southhampton Parkinson's Patients Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I presented my work on finding new drugs for Parkinson's Disease to a patient conference in Southhampton.
Year(s) Of Engagement Activity 2016
 
Description Press release on Autism 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release accompanying an article published on autism

It was picked up by Radio 4's Today programme, The Independent news paper and the New Scientist.
Year(s) Of Engagement Activity 2013
URL http://www.mrc.ac.uk/Newspublications/News/MRC009181
 
Description Press release on the genetics of handedness 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The work was picked up broadly by the international media.
http://www.newscientist.com/article/dn24200-genes-linked-to-lefthandedness-identified.html?cmpid=RSS|NSNS|2012-GLOBAL|online-news
http://www.guardian.co.tt/lifestyle/2013-09-15/genes-play-role-left-handedness
http://news.yahoo.com/lefty-righty-genes-handedness-found-165446637.html
http://www.foxnews.com/health/2013/09/13/lefty-or-righty-genes-for-handedness-found/

and many more.

International coverage!
Year(s) Of Engagement Activity 2013
URL http://www.ox.ac.uk/media/news_stories/2013/130913.html
 
Description Radio4 Today Programme interview 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact I was invited onto Radio 4's Today programme to discuss the findings in one of my recent papers on autism

I received a lot of contact from members of the pupblic seeking more ainformation about the work and with questions about autism.
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/programmes/b006qj9z
 
Description Represented Unit at MRC Centenary Mini Science Festival, Oxford, June 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Members of group helped to man the Unit stall/exhibits and talk to public at the MRC Centenary Mini Science Festival in Bonn Square, Oxford, 22 June 2013


Greater local public awareness of research work undertaken by the Unit and MRC
Year(s) Of Engagement Activity 2013
 
Description Science Festival - Cheltenham 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Group members helped to man the MRC exhibits and talk to public at the Cheltenham Science Festival June 2013


Greater public awareness of research work undertaken by the Unit and MRC
Year(s) Of Engagement Activity 2013
 
Description coverage in New Scientist on Autism work 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research in international publication

increased awareness of research output by public
Year(s) Of Engagement Activity 2013
URL http://www.newscientist.com/article/dn23684-web-of-autism-genes-pinpoints-key-players.html
 
Description coverage in New Scientist on handedness 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research by international media

Increased awareness of research output by public
Year(s) Of Engagement Activity 2013
URL http://www.newscientist.com/article/dn24200-genes-linked-to-lefthandedness-identified.html?cmpid=RSS...
 
Description coverage in The Guardian 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research by international media

Increased awareness of research output by public
Year(s) Of Engagement Activity 2013
URL http://www.guardian.co.tt/lifestyle/2013-09-15/genes-play-role-left-handedness
 
Description news coverage on Fox News 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research by international media

Increased awareness of research output by public
Year(s) Of Engagement Activity 2013
URL http://www.foxnews.com/health/2013/09/13/lefty-or-righty-genes-for-handedness-found/
 
Description news coverage on Yahoo! 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Coverage of research by international media

Increased awareness of research output by public
Year(s) Of Engagement Activity 2013
URL http://news.yahoo.com/lefty-righty-genes-handedness-found-165446637.html