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

Abstract

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.

FINDINGS:

We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable.

INTERPRETATION:

The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

• Authors: Gianpiero L Cavalleri, Michael E Weale, Kevin V Shianna, Rinki Singh, John M Lynch, Bronwyn Grinton, Cassandra Szoeke, Kevin Murphy, Peter Kinirons, Deirdre O'Rourke, Dongliang Ge, Chantal Depondt, Kristl G Claeys, Massimo Pandolfo, Curtis Gumbs, Nicole Walley, James McNamara, John C Mulley, Kristen N Linney, Leslie J Sheffield, Rodney A Radtke, Sarah K Tate, Stephanie L Chissoe, Rachel A Gibson, David Hosford, Alice Stanton, Tracey D Graves, Michael G Hanna, Kai Eriksson, Anne-Mari Kantanen, Reetta Kalviainen, Terence J O'Brien, Josemir W Sander, John S Duncan, Ingrid E Scheffer, Samuel F Berkovic, Nicholas W Wood, Colin P Doherty, Norman Delanty, Sanjay M Sisodiya, David B Goldstein
• Journal: The Lancet. Neurology (Lancet Neurol) Vol. 6 Issue 11 Pg. 970-80 (Nov 2007) ISSN: 1474-4422 [Print] England
• PMID: 17913586 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• GABRR2 protein, human
• KCNAB1 protein, human
• KCNMB4 protein, human
• Kv1.3 Potassium Channel
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits
• Nerve Tissue Proteins
• Receptors, GABA-A
• Receptors, GABA-B
• Synapsins
• ALDH5A1 protein, human
• Succinate-Semialdehyde Dehydrogenase

Topics

• Adult
• Case-Control Studies
• Chromosome Mapping
• Cohort Studies
• Epilepsy (genetics)
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• Humans
• Kv1.3 Potassium Channel (genetics)
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits (genetics)
• Nerve Tissue Proteins (genetics)
• Phenotype
• Polymorphism, Single Nucleotide
• Receptors, GABA-A
• Receptors, GABA-B (genetics)
• Seizures (genetics)
• Succinate-Semialdehyde Dehydrogenase (genetics)
• Synapsins (genetics)
• Syndrome