Population genetic studies of susceptibility and treatment response in epilepsy

Lead Research Organisation: University College London
Department Name: UNLISTED

Abstract

Epilepsy is an important condition, affecting 300,000 people in the UK alone. It increases the chances of early death, and is associated with psychological, social and financial disadvantages. The annual cost to the UK economy is over #500 million/year in direct costs alone, and much of this cost is due to epilepsy that is poorly controlled. Despite extensive research, we still know little about the causes of epilepsy and the causes of variable response to conventional antiepileptic drug treatment. Studies of rare families where multiple members are affected by epilepsy has revealed that mutations in specific genes (eg SCN1A, SCN1B, GABRG2) can cause some rare types of epilepsy. We have shown that common variation (polymorphism) in one (SCN1A ) of these genes (rather than rare mutation in that gene) also influences susceptibility to epilepsy in a large number of patients with epilepsy in whom there was not a clear inherited pattern of epilepsy. We have also shown that variation in another particular gene can influence to some degree how individuals patients might respond to antiepileptic drugs. These important findings show how common genetic variation, rather than rare genetic mutations, might have an effect on the risk of developing epilepsy and the response to antiepileptic drugs. Spurred on by these findings and the rapid advance in genetic knowledge and technology, we wish to study a larger range of carefully-selected genes in a large group of individuals with well-characterised epilepsy to identify other common variants that may have an important impact on susceptibility to and drug response in epilepsy. Once such genetic variants have been found, further detailed experiments can be devised to determine which variants are actually important at a clinical level and how such variants might exert their effects. Eventually, the resulting knowledge may lead to better treatment options, treatment tailored to the individual?s make-up, and perhaps even ways in which epilepsy might actually be prevented.
All the results from this project will be disseminated to the medical and scientific communities, related professionals and the lay public through the scientific media, conferences, press releases and patient support bodies, such as through the Department of Information and Education at the National Society for Epilepsy, an integral part of the working practices of the applicants.

Technical Summary

Epilepsy is an important condition: it affects 300,000 people in the UK, is associated with increased mortality and morbidity for patients, and costs the UK over #500 million/year. Significant problems plague epilepsy management: drug treatment is ineffective in 30% of patients, and an understanding of disease susceptibility is lacking, making prevention impossible. Heterogeneity in aspects of epilepsy suggests common genetic variation may contribute to disease susceptibility and treatment response. In large cohort studies, we showed genetic susceptibility to resistance to drug treatment (gene: ABCB1) and susceptibility to epilepsy with a history of febrile seizures (gene: SCN1A). The objectives of the proposed research are: (1) to identify genetic variants associated with susceptibility to, and drug response in, epilepsy using haplotype mapping on a large set of selected candidate genes; (2) to undertake directed genetic and clinical follow-up of our previous findings in one paradigmatic gene (SCN1A), and similar follow-up for other associations detected in this project. Large patient resources will be marshalled (we already have ~1,200 DNA samples): detailed phenotypic data will be collected for all patients on a bespoke interrogable secure database. Candidate genes will be carefully selected based on data from Mendelian epilepsies and pathophysiological considerations. Haplotype mapping (using HapMap, industrial collaborators and resequencing gene data) for these selected genes, will be undertaken in 2,000 well-characterised patients with epilepsy and 2,000 controls on a Taqman platform supported by the cooperative core. Statistical methods for choice of tagging single nucleotide polymorphisms and population genetic analyses will be applied, and genomic control for stratification (as in our ABCB1 work) will be employed. Gene interactions will be investigated. We will attempt to replicate identified associations in a second independent patient cohort. The general paradigm has already been undertaken for SCN1A in epilepsy and has identified an association between certain tagging SNPs and epilepsy with a history of febrile seizures. In this proposal, we will also follow these findings up for SCN1A, with directed genetic work to identify candidate causal variants, and clinical work to identify the time of action of such variants in the natural history of epilepsy and febrile seizures. Our SCN1A results show that genetic susceptibility can cut across current classifications, and could potentially identify at an early stage genetically at-risk individuals in whom targeted intervention could lead to prevention of the development of epilepsy. This is the long-term potential of the proposed research, to improve treatment and facilitate prevention.

Publications

10 25 50

 
Description SUDEP research
Amount $100,000 (USD)
Organisation CURE Epilepsy 
Sector Charity/Non Profit
Country United States
Start 02/2013 
End 07/2014
 
Description Strategic Award
Amount £4,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2015 
End 03/2020
 
Description Wellcome Trust Genomics of Common Diseases (Genome-wide association studies in partial epilepsies)
Amount £1,375,000 (GBP)
Funding ID 084730 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 07/2014
 
Title DNA resource and clinical database 
Description Web-based database for data collection for population genetic studies in epilepsy DNA resource 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact facilitation of multicentre studies 
 
Description CYP2C9 studies 
Organisation St Jude Children's Hospital
Country United States 
Sector Hospitals 
PI Contribution Case data and clinical interpretation
Collaborator Contribution Scientific input, intellectual input, study coordination
Impact Resulting manuscript : 19855097
Start Year 2009
 
Description EPIGEN 
Organisation Duke University
Country United States 
Sector Academic/University 
PI Contribution Contribution to leadership, research strategy, further funding and publications
Collaborator Contribution Additional cases and intellectual inputadditional cases and intellectual inputAdditional cases, intellectual input and genotyping
Impact Several manuscripts as detailed in first section
 
Description EPIGEN 
Organisation Free University of Brussels
Country Belgium 
Sector Academic/University 
PI Contribution Contribution to leadership, research strategy, further funding and publications
Collaborator Contribution Additional cases and intellectual inputadditional cases and intellectual inputAdditional cases, intellectual input and genotyping
Impact Several manuscripts as detailed in first section
 
Description EPIGEN 
Organisation Royal College of Surgeons in Ireland
Country Ireland 
Sector Learned Society 
PI Contribution Contribution to leadership, research strategy, further funding and publications
Collaborator Contribution Additional cases and intellectual inputadditional cases and intellectual inputAdditional cases, intellectual input and genotyping
Impact Several manuscripts as detailed in first section
 
Description Levetiracetam pharmacogenomics 
Organisation UCB Pharma
Country United Kingdom 
Sector Private 
PI Contribution Acquired and processed data
Impact Publication and further grant support for levetiracetam genome-wide pharmacogenomics Output: 18977120
 
Description SCN1A replication study 
Organisation University of Otago
Department Department of Medicine
Country New Zealand 
Sector Academic/University 
PI Contribution Data provision, intellectual input
Collaborator Contribution Additional cases
Impact Manuscript: 19949041
Start Year 2009
 
Description AGMs of epilepsy charities 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Description of research activity and outcome and potential to patients and carers

Minor fundraising
Year(s) Of Engagement Activity 2007,2008,2009
 
Description magazine/periodical 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Description of research and potential

Interest, new recruits, minor funding
Year(s) Of Engagement Activity 2007,2008,2009