Evaluating candidate genes in common epilepsies and the nature of evidence.
Very few genetic associations for idiopathic epilepsy have been replicated and this has tempered enthusiasm for the results of genetic studies in epilepsy. What are the reasons for lack of replication? While type 1 error, population stratification, and multiple testing have been discussed extensively, the importance of genetic heterogeneity has been relatively neglected. In the first part of this review, we explore the sources of genetic heterogeneity and their importance for epilepsy genetic studies. In the second part, we review alternatives to the simple law of replication, revisiting Bradford Hill's guidelines for evidence of causality. A coherence perspective is applied to three examples. We conclude that adopting the perspective of integrating coherent and consistent evidence from different experimental approaches is a more appropriate requirement for proceeding to functional studies.
Pal
Deb K
DK
Epidemiology Division, Department of Psychiatry, Columbia University Medical Center, New York, New York 10032, USA. dkp28@columbia.edu
Strug
Lisa J
LJ
Greenberg
David A
DA
D004827:Epilepsy / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D017408:Guidelines as Topic; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics*; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards / Q000706:statistics & numerical data
D007473:Ion Channels