Unraveling the genetics of common epilepsies: approaches, platforms, and caveats.

With no known intervention to prevent or cure epilepsy, treatment is primarily symptomatic and requires long-term administration of medications to suppress seizure occurrence. Current antiepileptic drugs (AEDs) are ineffective in one-third of patients (Kwan and Brodie, 2000). Such therapeutic inadequacy is largely due to our insufficient understanding of the basic molecular pathophysiological processes that underlie epileptogenesis. Breakthroughs are needed in the identification of new molecular targets that will translate to novel intervention approaches. Discovering genetic variants that increase the susceptibility to disease is a promising avenue to identifying such targets. However, early candidate gene-based studies in epilepsy proved ineffective in identifying genetic risk factors for the non-Mendelian, complex epilepsies, which represent >95% of clinically encountered epilepsy. Furthermore, genome-wide association studies (GWAS) of epilepsy patients have been largely negative, with the exception of several putative susceptibility loci discovered in Han Chinese focal epilepsy and European Caucasian GGE patients (Kasperaviciute et al., 2010; Guo et al., 2012; Consortium et al., 2012). Results of these GWAS suggest that, similar to other common diseases, associations with common single nucleotide variants (SNV) appear likely to account for a small fraction of the heritability of epilepsy, thus fuelling the effort to also search for alternative genetic contributors, with a recent increased emphasis on rare variants with larger effects (Manolio et al., 2009). It is possible that both common and rare variants contribute to an increased susceptibility to common epilepsy syndromes (Mulley et al., 2005). We review the approaches that have been taken to identify genetic risk markers of the common epilepsy syndromes, the experimental platforms, and their caveats. We discuss current technologies and analytical frameworks that might expedite the discovery of these variants by leveraging advances in microarray-based, high-throughput, genotyping technology, and complementary interdisciplinary expertise of study teams including the need for meta-analyses under global collaborative frameworks. We briefly discuss the analytical options made available through rapid advances in sequencing and other genomic technologies.