Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

“…One GWAS on idiopathic epilepsy did show evidence for association at four separate loci (1q43, 2p16.1, 2q22.3, and 17q21.32). However, as has been the pattern in other diseases, the results suggested that the alleles discovered accounted for a very small portion of the relative risk [67]. (Of note, none of the genes of interest mentioned were channel genes.)…”

Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

“…In our study, neuroblastoma SH-SY5Y cell viability was reduced by pathogenic HttQ103-GFP expression, and VRK2 overexpression increased HttQ103-GFP aggregate formation in SH-SY5Y cells, suggesting that the level of active VRK2 in neuronal cells may be important for the onset and progression of polyQ diseases. Moreover, genome-wide association studies have revealed that VRK2 has emerged as one of the risk factors against neurological disorders, including schizophrenia (43,44) and epilepsy (45,46). VRK2 expression, however, is known to be much higher in actively proliferating cells and is maintained at a low level in the brain (47).…”

An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population

“…The selected SNPs are located within genes which encode sodium ion channel SCN1A (rs1685381 and rs8191987), SCN8A (rs303778), SCN3B (rs1783901), potassium ion channel KCNQ2 (rs1801545), KCNAB1 (rs992353), and glutamate receptor GRM4 (rs4711374, rs1466650, rs937039, rs2499697, rs2451357, rs9380405, rs745501, rs11753413, rs2451334, and rs2029461). Furthermore, 10 additional loci including VRK2 (rs13026414), COPZ2 (rs72823592), ZEB2 (rs10496964), CHRM3 (rs12059546), SCN1A (rs11890028), PCDH7 (rs28498976 and rs1044352), GOLIM4 (rs111577701), GABRA2 (rs535066), and MMP8 (rs1939012), found to be associated with epilepsy in GWAS, were included in the study [Steffens et al, 2012 …”

“…Recently conducted genome-wide association studies (GWAS) and meta-analyses facilitated the identification of new loci associated with the risk of epilepsy, both in the genes encoding ion channels and the genes unrelated to "channelopathies" [Steffens et al, 2012; International League against Epilepsy Consortium on Complex Epilepsies, 2014].…”