Blinders, phenotype, and fashionable genetic analysis: A critical examination of the current state of epilepsy genetic studies

Abstract

SUMMARYAlthough it is accepted that idiopathic generalized epilepsy (IGE) is strongly, if not exclusively, influenced by genetic factors, there is little consensus on what those genetic influences may be, except for one point of agreement: epilepsy is a ''channelopathy.'' This point of agreement has continued despite the failure of studies investigating channel genes to demonstrate the primacy of their influence on IGE expression. The belief is sufficiently entrenched that the more important issues involving phenotype definition, data collection, methods of analysis, and the interpretation of results have become subordinate to it. The goal of this article is to spark discussion of where the study of epilepsy genetics has been and where it is going, suggesting we may never get there if we continue on the current road. We use the long history of psychiatric genetic studies as a mirror and starting point to illustrate that only when we expand our outlook on how to study the genetics of the epilepsies, consider other mechanisms that could lead to epilepsy susceptibility, and, especially, focus on the critical problem of phenotype definition, will the major influences on common epilepsy begin to be understood.

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

“…Although many leads were generated through examining channel genes in epilepsy, the evidence for their involvement in any but the rare families in which they were found has been unconvincing. Overall, studies seeking to independently observe the effects reported for channel genes in new epilepsy samples failed to turn up any significant findings [54]. This called into question the true generalizability of the channel gene model of epilepsy etiology.…”

Comment on “Blinders, phenotype, and fashionable genetic analysis: A critical examination of the current state of epilepsy genetic studies”

“…Professor Greenberg's main points about heterogeneity and phenotype definition serve as salutary reminders about checking the bungee cord as the field prepares to plunge into ''big science'' projects like genomewide association studies (GWAS), meta-analysis, and whole genome sequencing (Greenberg & Subaran, 2010).…”

“…Several new powerful genetic methods, including genome-wide sequencing and association analysis, are now ''routinely'' available to probe the genetic architecture of epilepsy, and the contribution from Greenberg and Subaran (2010) to the debate on how best to apply these methods is both timely and welcome.…”

“…Epilepsy phenotype is not an absolute concept, but a device that can be flexibly adapted to fit the purpose at hand, be that presurgical assessment or an attempt to get ''closer'' to the molecular genetic origins. Therefore, Greenberg and Subaran (2010) and others have proposed that restricting the dimension of a phenotype is the best way to maximize the chances of detecting epilepsy genetic risk factors. However, others might point to the fact that the single most important epilepsy gene yet discovered, SCN1A, was identified precisely because it was recognized that heterogeneous forms of epilepsy might share a common genetic etiology (Scheffer & Berkovic, 1997).…”

Epilepsy: Selenium and Aging

“…Furthermore, even if epilepsy could be divided into groups based on the respective, underlying cause, it would still be difficult to determine the genetic influence because of changes across clinical subgroups and amongst families. However, some types of epilepsy have been shown to have strong genetic components (Greenberg and Subaran 2011): 1) partial epilepsy has been linked to chromosome 10 q; 2) benign familial neonatal convulsions have been mapped to chromosome 20 q and another locus found on 8q; 3) a progressive form of myoclonus epilepsy has been localized to chromosome 21 q; 4) juvenile myoclonic epilepsy has been associated with regions of chromosome 6. Interestingly, the types of epilepsy syndromes that have genetic linkage evidence are a very small proportion of all epilepsy cases and no genetic basis has been found for most types of epilepsy.…”