Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study.

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

Background: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy.

Methods: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy.

Multidrug resistance in epilepsy: a pharmacogenomic update.

Multidrug resistance is one of the most serious problems in the treatment of epilepsy and is likely to have a complex genetic and environmental basis. Various experimental data support the hypothesis that overexpression of antiepileptic drug transporters may be important. However, key questions concerning their functionality remain unanswered.

Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.

An intronic polymorphism in the SCN1A gene, which encodes a neuronal sodium-channel alpha subunit, has been previously associated with the dosing of two commonly used antiepileptic drugs that elicit their pharmacologic action primarily at this ion-channel subunit. This study sought to characterize the functional effects of this polymorphism on alternative splicing of SCN1A and to explore the potential for modulating the drug response in the pharmacologically unfavorable genotype by identification of a splice modifier acting on SCN1A. The effects of the genotype at the SCN1A IVS5N+5 G-->A polymorphism on SCN1A splice-variant proportions and the consequences of increased expression of splice modifiers were investigated both in human temporal neocortex tissue and in a cellular minigene expression system.

A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.

Objectives: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target.

Methods: We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin.

A novel test of conditioned inhibition correlates with personality measures of schizotypy and reward sensitivity.

Conditioned inhibition is demonstrated when the meaning of one signal (conditioned stimulus, CS) is qualified by another (conditioned inhibitor, CI). Whilst the CS presented alone reliably predicts the outcome (unconditioned stimulus, US), when presented in conjunction with the CI the otherwise expected US will not occur. Conditioned inhibition has long been established in animal research but there have been difficulties in establishing reliable procedures suitable for use in human research.

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates.

Will tomorrow's medicines work for everyone?

Throughout much of the world, 'race' and 'ethnicity' are key determinants of health. For example, African Americans have, by some estimates, a twofold higher incidence of fatal heart attacks and a 10% higher incidence of cancer than European Americans, and South Asian- or Caribbean-born British are approximately 3.5 times as likely to die as a direct result of diabetes than are British of European ancestry.

Pharmacogenetics goes genomic.

Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up.