Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?
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.
Cavalleri
Gianpiero L
GL
Department of Biology, Institute of Neurology, University College London, London, UK.
Lynch
John M
JM
Depondt
Chantal
C
Burley
Mari-Wyn
MW
Wood
Nicholas W
NW
Sisodiya
Sanjay M
SM
Goldstein
David B
DB
D000682:Amyloid / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D004399:Dynorphins / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006624:Hippocampus; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000235:genetics; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D015203:Reproducibility of Results
D000682:Amyloid; D001057:Apolipoproteins E; D004399:Dynorphins; D007375:Interleukin-1; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D011978:Receptors, Nicotinic; C106350:GABRR2 protein, human; C512656:PRNP protein, human; C036448:pre-prodynorphin