Genetic Association Studies in Epilepsy: “The Truth Is Out There”

Abstract

Summary: Success has been achieved in identifying many mutations in rare monogenic epilepsy syndromes by using linkage analysis, but dissecting the genetic basis of common epilepsy syndromes has proven more difficult. Common epilepsies are genetically complex disorders believed to be influenced by variation in several susceptibility genes. Association studies can theoretically identify these genes, but despite more than 50 association studies in epilepsy, no consistent or convincing susceptibility genes have emerged, leading to scepticism about the association-study approach. We review the results of existing association studies in focal epilepsies, generalized epilepsies, febrile seizures, and epilepsy pharmacogenetics. By using an illustrative example, we discuss how methodologic issues of sample size, selection of appropriate controls, population stratification, and significance thresholds can lead to bias and falsepositive associations; the importance of biologic plausibility also is emphasized. Newer methodologic refinements for association studies, such as use of two control groups, genomic control, haplotyping, and use of two independent datasets, are discussed. A summary of existing guidelines and a checklist for planning and appraising such association studies in epilepsy is presented. We remain cautiously optimistic that with methodologic refinements and multicenter collaborations with large sample sizes, association studies will ultimately be useful in dissecting the genetic basis of common epilepsy syndromes.

Non-replication of association studies: “pseudo-failures” to replicate?

“…For examples on the use of different sample sizes in replication calculations, based on initial effect sizes, see Tversky and Kahneman 30 and Heils. 31 Regarding the second condition, Tan et al 32 point out, "Estimates of effect size will tend to regress to the true effect size in subsequent [association] studies, which is usually less extreme." The same feeling has been echoed elsewhere, 7,8,33 and Göring et al 5 have provided a theoretical justification.…”

Genes e epilepsia I: epilepsia e alterações genéticas

“…Nessas epilepsias, como o efeito da alteração em um gene contribui muito discretamente para o fenótipo final, o poder estatístico para detecção de ligação entre o gene e o traço epiléptico fica comprometido. Só recentemente é que estudos de associação têm sido usados, como alternativa aos estudos de ligação, para identificar genes associados à epilepsia e a outras desordens complexas 19,34 . Estes estudos buscam detectar alelos que contribuem para a predisposição ou proteção à epilepsia por meio da investigação de diferenças significativas na freqüência de polimorfismos entre indivíduos epilépticos e indivíduos normais de uma mesma população.…”

“…Muitos desses estudos, porém, não têm sido reprodutíveis devido a limitações como tamanho da amostra, falta de grupo controle apropriado e ausência de análises independentes em outras populações 34 . Assim, os estudos de associação acoplados a uma validação funcional dos polimorfismos são os que têm maior valor informativo.…”

The Correlation Between IL-1β and IL-10 Levels in Estimating The Risk of Febrile Seizures

“…Fever itself is a risk factor in febrile seizures as rising body temperatures provoke seizure threshold and neural excitability as it effects on ion channels, cellular metabolism and ATP production [3,5,6].…”

“…At the same time, it enhances the inhibitory, tolerance inducing, and 'scavenger' functions of these cells. In fact, IL-10 inhibits the release of pro-inflammatory mediators from monocytes/ macrophages, and therefore inhibits the LPS-and IFN-γ-induced secretion of TNF-α, IL-1β, IL-6, IL-8, G-CSF, and GM-CSF [6]. IL-10 inhibits the synthesis of IL-12, thereby; it hampering the development of Th1 immunity [13,14].…”