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

Abstract

Although 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.

Figure 1. Interaction, convergence between brain development, epilepsy and autism

Brain development is a state of heightened synaptic excitability, to permit the critical period of synaptic plasticity. When disrupted, it can either generate early cognitive disorders such as autism, or if synaptic excitability is excessive, epilepsy. Epilepsy is of high prevalence in the immature brain due to the heighted synaptic tone. Normal brain development, autism, and epilepsy all share in common synaptic activity, and further understanding of how epilepsy and autism may share similar dysregulation of synaptic elements may lead to new therapies. In addition, it is not yet known whether the epileptic seizures themselves, by way of dysregulating synaptic activity at a critical developmental stage, may contribute to autism.

Figure 2. Connectomics is a method to assess global brain connectivity as well as meta-patterns of brain activity

A. Connectomics can computationally integrate any combination of multiple modalities, including clinical observation of neurobehavior and genomics, neurophysiological including electroencephalography (EEG), evoked potentials (EP), and magnetoencephalography (MEG), as well as structural including magnetic resonance imaging (MRI), Diffusion tensor imaging (DTI), and functional MRI imaging (fMRI). B. Example of a connectivity map for the left hemisphere, using data obtained from fMRI and DTI. Individual brain regions are indicated by dots, and the strength of connections denoted by thickness of the line connecting these regions. (Figure 2B Reprinted with permission from PLoS Biol(Hagmann et al. 2008).