Brain Advance Access originally published online on May 11, 2005
Brain 2005 128(8):1832-1840; doi:10.1093/brain/awh524
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Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?
1 Department of Biology, 2 Department of Molecular Neurosciences and 3 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK and 4 IGSP Center for Population Genomics and Pharmacogenetics, Duke University, Durham, North Carolina, USA
Correspondence to: David Goldstein at d.goldstein{at}duke.edu or Sanjay Sisodiya at s.sisodiya{at}ion.ucl.ac.uk
Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.
Key Words: epilepsy; TLE; epilepsy genetics; association; replication
Abbreviations: FS = febrile seizures; HS = hippocampal sclerosis; IGE = idiopathic generalized epilepsy; TLE = temporal lobe epilepsy
Received October 11, 2004. Revised March 30, 2005. Accepted April 4, 2005.
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