Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis.

Hiltrud Muhle, Sarah von Spiczak, Verena Gaus, Serife Kara, Ingo Helbig, Jochen Hampe, Andre Franke, Yvonne Weber, Holger Lerche, Ailing A Kleefuss-Lie, Christian E Elger, Stefan Schreiber, Ulrich Stephani, Thomas Sander
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Epilepsy research : international multidisciplinary journal devoted to experimental and clinical epileptology
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GRM4 encoding the group III metabotropic glutamate receptor 4 (mGluR4), is located on the chromosomal segment 6p21.3 where tentative susceptibility loci for Juvenile Myoclonic Epilepsy (JME) and Photoparoxysmal Response (PPR) have been mapped. The present candidate gene study examined if variation in GRM4 confers susceptibility to IGE.The case-control association sample included 564 unrelated IGE patients and 733 population controls of German descent. Association analysis was carried out for 17 single nucleotide polymorphisms (SNPs) covering the genomic GRM4 sequence for all IGE patients as well as for two common IGE subsyndromes [Juvenile Myoclonic Epilepsy (JME, n=215) and Childhood Absence Epilepsy (CAE, n=175)]. Sequence analysis was performed in 85 IGE and 42 PPR cases and 44 controls.Nominally significant associations were detected between IGE and seven GRM4 SNPs (with P-values ranging from 0.037 to 0.0036), between JME and five SNPs (P=0.042-0.0106), and between CAE and two SNPs (P=0.0466-0.0021). Four novel SNPs were identified by sequence analysis.Our association findings support the hypothesis that GRM4 sequence variants might confer low-risk effects to the etiology of IGE. A minor pathogenetic contribution of the examined variants is possible. These exploratory findings warrant further replication analyses.