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

Authors

  • David A. Greenberg,

    1. Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health and Department of Psychiatry and New York State Psychiatric Institute, Columbia University Medical Center, New York, New York, U.S.A.
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  • Ryan Subaran

    1. Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health and Department of Psychiatry and New York State Psychiatric Institute, Columbia University Medical Center, New York, New York, U.S.A.
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Address correspondence to David A. Greenberg, Ph.D., Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health and Department of Psychiatry and New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032, U.S.A. E-mail: dag@shallot.cpmc.columbia.edu

Summary

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.

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