Neurological Disease Genomics
Lead Research Organisation:
MRC Functional Genetics Unit
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.
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.
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.
People |
ORCID iD |
Caleb Webber (Principal Investigator) |
Publications


Andrews T
(2015)
The clustering of functionally related genes contributes to CNV-mediated disease.
in Genome research


Brandler WM
(2013)
Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
in PLoS genetics

Ferry Q
(2014)
Diagnostically relevant facial gestalt information from ordinary photos.
in eLife

Gormley P
(2016)
Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.
in Nature genetics


Hedegaard A
(2020)
Pro-maturational Effects of Human iPSC-Derived Cortical Astrocytes upon iPSC-Derived Cortical Neurons.
in Stem cell reports

Heger A
(2013)
GAT: a simulation framework for testing the association of genomic intervals.
in Bioinformatics (Oxford, England)

Hoerder-Suabedissen A
(2013)
Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia.
in Proceedings of the National Academy of Sciences of the United States of America
Description | DPhil Clarendon Fund Scholarship (TA) |
Amount | £31,798 (GBP) |
Organisation | University of Oxford |
Department | Clarendon Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2014 |
Description | DPhil NSERC Julie Payette Scholarship (TA) |
Amount | $25,000 (CAD) |
Organisation | Natural Sciences and Engineering Research Council of Canada (NSERC) |
Sector | Public |
Country | Canada |
Start | 09/2011 |
End | 09/2012 |
Description | DPhil Nuffield Department of Medicine (WB) |
Amount | £44,330 (GBP) |
Organisation | University of Oxford |
Department | Nuffield Department of Medicine |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2013 |
Description | DPhil Somerville Graduate Scholarship (TA) |
Amount | £15,191 (GBP) |
Organisation | University of Oxford |
Department | Somerville College |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2014 |
Description | DPhil Wellcome Trust (JS) |
Amount | £114,998 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2014 |
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 | Innovative Medicines Initiative StemBANCC grant |
Amount | € 700,000 (EUR) |
Funding ID | 115439-2 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 09/2012 |
End | 09/2017 |
Description | Oxford Parkinson's Disease Consortium 2 |
Amount | £250,000 (GBP) |
Organisation | Parkinson's UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
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 | Understanding the role of copy number variation in developmental delay |
Organisation | Children's Hospital of Philadelphia |
Department | Division of Human Genetics and Molecular Biology |
Country | United States |
Sector | Hospitals |
PI Contribution | We provided the functional genomics analyses |
Collaborator Contribution | In this collaboration, we analysed genetic abnormalities identified in children with developmental delay by our collaborators, and we found signficant functional insight in to how these genetic abnormalities cause these children's symptoms. |
Impact | A significant primary publication listed under our publications (PMID 21147756). |
Start Year | 2010 |
Description | Understanding the role of small insertions and deletions in human genetic variation |
Organisation | Emory University |
Department | Department of Biochemistry |
Country | United States |
Sector | Academic/University |
PI Contribution | We provided the functional analysis and interpretation |
Collaborator Contribution | Our collaborators identified a tremendous amount of hitherto unknown genetic variation within apparently healthy individuals cause by small insertions and deletions in their genomes. We analysed the likely functional impact of such variants and provided a consequential interpretation of the variation they identified. |
Impact | A significant publication as reported elsewhere in this form (PMID 21460062) |
Start Year | 2010 |
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 |