Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study - 16/08/11

Doi : 10.1016/S1474-4422(07)70247-8

Gianpiero L Cavalleri, PhD ^a, Michael E Weale, PhD ^f, Kevin V Shianna, PhD ^f, Rinki Singh, MD ^b,^c, John M Lynch, MD ^b,^c, Bronwyn Grinton, BSc ^j, Cassandra Szoeke, PhD ⁱ, Kevin Murphy, MD ^a, Peter Kinirons, MD ^a, Deirdre O’Rourke, MD ^a, Dongliang Ge, PhD ^f, Chantal Depondt, PhD ^p, Kristl G Claeys, PhD ^o, Massimo Pandolfo, MD ^p, Curtis Gumbs, BS ^f, Nicole Walley, BS ^f, James McNamara, MD ^m, John C Mulley, PhD ^g, Kristen N Linney, RN ^f, Leslie J Sheffield, FRACP ^h, Rodney A Radtke, MD ⁿ, Sarah K Tate, PhD ^b, Stephanie L Chissoe, PhD ^s,^t, Rachel A Gibson, PhD ^s,^t, David Hosford, MD ^s,^t, Alice Stanton, PhD ^l, Tracey D Graves, MRCP ^e, Michael G Hanna, FRCP ^e, Kai Eriksson, MD ^q,^r, Anne-Mari Kantanen, MD ^q,^r, Reetta Kalviainen, MD ^q,^r, Terence J O’Brien, MD ⁱ, Josemir W Sander, MD, FRCP ^b,^d, John S Duncan, FCRP ^b,^c, Ingrid E Scheffer, PhD ^j,^k, Samuel F Berkovic, MD ^j, Nicholas W Wood, FRCP ^e, Colin P Doherty, MRCPI ^a, Norman Delanty, FRCPI ^a, Sanjay M Sisodiya, PhD ^b,^c,^⁎ , David B Goldstein, PhD ^f,^⁎
^a Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland Research Institute, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
^b Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK
^c National Society for Epilepsy, Chalfont-St-Peter, UK
^d Epilepsy Institutes of the Netherlands Foundation, Heemstede, Netherlands
^e Department of Molecular Neuroscience, Institute of Neurology, University College London, London
^f Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, Durham, NC, USA
^g Department of Genetic Medicine, Women’s and Children’s Hospital, and School of Molecular and Biomedical Sciences, and School of Paediatrics and Health Sciences, University of Adelaide, Adelaide, Australia
^h Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Australia
ⁱ Departments of Medicine and Neurology, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
^j Department of Medicine, University of Melbourne, Melbourne, Australia
^k Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia
^l Blood Pressure Unit, Beaumont Hospital, and Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland Research Institute, Dublin, Ireland
^m Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
ⁿ Department of Medicine, Duke University Medical Center, Durham, NC, USA
^o Neurogenetics Group, Department of Molecular Genetics, University of Antwerp, and Department of Neurology, University Hospital Antwerp, Antwerp, Belgium
^p Department of Neurology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium
^q Kuopio Epilepsy Center, Department of Neurology, University Hospital of Kuopio, Kuopio
^r Medical School, University of Tampere, Tampere, Finland
^s GlaxoSmithKline, Research Triangle Park, NC, USA
^t GlaxoSmithKline, New Frontiers Science Park, Harlow, UK

^*Correspondence to: Sanjay Sisodiya, Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK^**David Goldstein, Institute for Genome Sciences and Policy, Center for Population Genomics and Pharmacogenetics, Duke University, 101 Science Drive, Box 3382, Durham, NC 27708, USA

Summary

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.

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Plan

Selection of candidate genes

SNP selection strategy

Genotyping

Statistical analysis

Role of the funding source

Results

Discussion

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Vol 6 - N° 11

P. 970-980 - novembre 2007 Retour au numéro

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Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study - 16/08/11

Summary

Background

Methods

Findings

Interpretation

Plan

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