Approximately 3% of the general population is affected by epilepsy during lifetime,
making epilepsy one of the most common neurological diseases. Genetic generalized
epilepsies (GGE) are the most common of genetic epilepsies and account for 20-30%
of all epilepsies. GGE is subdivided into genetically determined subgroups with
gradual transition, including genetic absence epilepsies (GAE), juvenile myoclonic
epilepsy (JME), and epilepsy with generalized tonic-clonic seizures (EGTCS). In spite
of a high heritability rate of 80% and a predominant genetic etiology, the genetic
factors predisposing to GGE are still mostly unknown. In the present study, we
carried out association studies to investigate whether genomic microdeletions and
common susceptibility variants increase risk for GGE.
To test the common disease/common variant hypothesis, genome-wide association
studies (GWAS) were performed in several GGE cohorts using case-control and
family-based study designs. For analysis, all patients were either pooled or stratified
according to the subgroup they belong to in order to detect common or subgroupspecific
risk factors, respectively. The GWAS comprised a case-control cohort of
1,523 European GGE patients and 2,454 German controls and a sample cohort of 566
European parent-offspring trios. Meta-GWAS analyses revealed significant
association (P < 5.0 × 10-8) with GGE at 2p16.1 (rs35577149, meta-analysis P = 1.65E-08, OR[C] = 0.78, 95% CI 0.71 - 0.86). Significant association with JME was
detected at 1q43 (rs12059546, meta-analysis P = 2.27E-08, OR[G] = 1.53, 95% CI
1.33 - 1.78). Suggestive evidence for association (P < 1.0E-05) was found for GGE
at 8q12.2 (rs6999304, meta-analysis P= 1.77E-06, OR[G] = 1.33, 95% CI 1.17 -
1.51) and for GAE at 2q22.3 (rs75917352, meta-analysis P = 1.41E-07, OR[T] =
0.67, 95% CI 0.58 - 0.79). The associated regions harbor high-ranking candidate
genes: CHRM3 at 1q43, VRK2 at 2p16.1, and ZEB2 at 2q22.3. Further replication
efforts are necessary to elucidate whether these positional candidate genes
contribute to the heritability of the common GGE syndromes.
Exploring the rare variant/common disease hypothesis, we investigated the impact
of six recurrent microdeletions on the genetic risk of GGE at the genomic hotspot
regions 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2, which had been implicated as rare genetic risk factors in a wide range of neurodevelopmental
disorders. Recurrent microdeletions were assessed in 1,497 European GGE patients,
5,374 controls, and 566 GGE trios using high-resolution SNP microarrays.
Considering all six microdeletion hot spots together, we found a significant excess of
these microdeletions in 2,563 GGE patients versus 5,940 controls (P < 2.20E-16,
OR = 7.65, 95% CI 4.59 - 13.18). Individually, significant associations with GGE were
observed for the microdeletions at 15q11.2 (P = 1.12E-4, OR = 3.59, 95% CI 1.80
- 7.25), 15q13.3 (P = 5.48× 10−9) and 16p13.11 (P = 4.42E-06, OR = 17.39, 95% CI
3.86 - 159.88).
In a candidate-gene approach, we tested whether exon-disrupting/removing
microdeletions in the genes encoding NRXN1 and RBFOX1 confer susceptibility for
GGE. We found a significant association with GGE at both loci (NRXN1: P = 0.0049;
RBFOX1: P = 0.0083). However, high phenotypic variability and incomplete
penetrance, resulting in apparently imperfect segregation, indicate that partial
NRXN1 and RBFOX1 deletions represent susceptibility factors rather than highly
penetrant mutations.
The present study substantiates a role of both genomic microdeletions and common
susceptibility variants in the genetic predisposition of common GGE syndromes. We
strengthened the statistical evidence for associations of genetic variants at 1q43,
2p16.1, and 2q23.2 with GGE syndromes and identified a novel susceptibility locus
at 8q12.2. Although individually rare, the associations of all microdeletions at
15q11.2, 15q13.3, 16p13.3, NRXN1, and RBFOX1 taken together contribute
significantly to the genetic variance of GGE
