Co-sponsored by National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS-NIH), the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE)
A conference on "Molecular Analysis of Complex Genetic Epilepsies," co-sponsored by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS-NIH), the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), was convened to establish a sound scientific basis for next steps in genetic analysis of the complex genetic epilepsies using molecular methods. Participants reviewed the current status of knowledge about genetic factors in the epilepsies, and current and potential methods (molecular and statistical) for studying structural and functional genomics in complex disorders. The goal was to develop recommendations appropriate for future research on those epilepsies that are genetically complex.
Scientists and clinicians from nearly a dozen countries discussed epilepsy in terms of its classification, epidemiology, evidence for genetic etiology, neurobiology, phenotype/genotype correlations, and the use of linkage and association studies to identify candidate genes with the goal of elucidating gene functions. The ultimate goal of these research efforts is to integrate and apply clinical and molecular approaches to the study of the epilepsy syndromes to develop genomics-based drug therapies.
Much of the focus of the meeting was on elucidating the molecular and genetic basis of the common epilepsies that have a significantly increased familial risk, but at a level that does not fit simple Mendelian modes of inheritance-a category often called "complex diseases" by geneticists. The idiopathic generalized epilepsies (IGEs) form the largest single category of such epilepsies. A careful review of appropriate molecular methods for the IGEs should be applicable to other complex genetic epilepsies.
Ruth Ottman (Columbia University), Sam Berkovic (University of Melbourne), and Mark Gardiner (University College, London) emphasized the importance of classification and genetic epidemiology of epilepsies. Any large-scale study must resolve which epilepsy phenotypes should be ascertained as well as what clinical documentation is required. For example, should molecular analysis be guided by epilepsy syndrome, seizure type, or EEG pattern? Another problem arises from the overlapping of syndrome phenotypes. Thus, it is not clear which subgroup or combination of subgroups constitutes the most appropriate phenotype for genetic analysis.
Jeff Noebels (Baylor College of Medicine) and Mark Leppert (University of Utah) addressed the neurobiology of the epilepsies and the identification of candidate genes in humans and mouse. The features that define the epileptic discharge process-hyperexcitability and hypersynchrony-are precisely those that are critical to normal nervous system function. Most of the genes that have been identified so far for the rare monogenic epilepsies encode ion channel proteins, which affect neuronal excitability. Genes involved in nervous system development may also be important. Some of the many genes that influence susceptibility can be expected to have a major effect, while others may function as modulators.
Analysis and interpretation of linkage and association studies must deal with genetic heterogeneity involving either mutations at different genetic loci, or different mutations at the same genetic locus. Jurg Ott (Rockefeller University), Lon Cardon (Wellcome Trust Centre, Oxford), and Joan Bailey-Wilson (NHGRI) discussed the methods used in such studies, including problems with statistical power, setting significance levels, replication, consistency of measurements within and among studies, ascertainment bias, stratification effects, and errors in genotyping and phenotyping.
Ken Weiss (Pennsylvania State University) presented an "outsider's view" of epilepsy in the context of complex genetic disease. Confounding of frequency and effect size has to be considered, as well as the combinatorial dose-like effects of many genes. He also suggested that somatic mutation may play a role in a cellular-based, often segmentally localized, disorder like epilepsy.
Kerstin Lindblad-Toh (MIT Center for Genome Research) described haplotype-based association studies as a potentially powerful approach to epilepsy gene mapping, based on linkage disequilibrium (LD) between disease-causing mutations and the haplotypes from which they arose. A vast majority of the human genome can be parsed into haplotype blocks. Within blocks, haplotype diversity is limited; thus they can be used to test the role of common genetic variants in human disease. Lon Cardon (Oxford University) discussed optimal sampling designs for haplotype mapping, as well as the number of samples required for map building, the SNPs needed for genotyping, the requirements for de novo disease-specific detection, and issues pertaining to population variability.
Participants discussed the need, feasibility, and possible strategies for large-scale collaborative efforts to analyze the molecular basis of the genetically complex epilepsies. Collaborative studies could provide the opportunity to expand available sample size beyond what has been possible in previous studies. Decisions about the optimal design and analytic approaches for such collaborative studies are extremely difficult, and a consensus has not yet been reached on this point. Some of the possibilities to be considered include linkage, association, or a combination of the two, with the use of microsatellites, SNPs, or SNP-based haplotypes, in genome-wide or candidate gene studies. In addition, the practical issues to be resolved include the selection of phenotypes for initial analysis, development of methods to standardize clinical diagnosis and classification, adherence to basic principles of informed consent and privacy protections, possible mechanisms for DNA banking across international borders, and assurance that the efforts of all investigators are recognized appropriately.
A complete report of the conference is being prepared for publication.
Last updated April 8, 2011