Genetic factors play a predominant role in about 40% of all epilepsies (ILAE Commission on Classification and Terminology, 1989). Genetic generalized epilepsies (GGEs, formerly called the idiopathic generalized epilepsies) represent the most common group of genetically determined epilepsies; they account for approximately 20–30% of all epilepsies (Jallon et al., 2001). The GGE syndromes are characterized by age-related recurrent unprovoked generalized seizures in the absence of detectable brain lesions or metabolic abnormalities (ILAE Commission on Classification and Terminology, 1989; Berg et al., 2010). The common classical GGE syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures (EGTCS) alone (Nordli, 2005). The electroencephalographic signature is generalized spike-wave discharges (GSW-EEG), which reflect a synchronized hyperexcitability state of thalamocortical circuits (Blumenfeld, 2005).
Despite heritability estimates of >80% obtained by twin studies (Berkovic et al., 1998; Kjeldsen et al., 2003), the genetic factors predisposing to common GGE syndromes remain elusive (Gardiner, 2005). The genetic architecture of GGEs most likely represents a biologic continuum, in which a small fraction (1–2%) follows monogenic inheritance, whereas the majority of GGE patients presumably display an oligogenic/polygenic predisposition. Moreover, twin and family studies provide evidence for genetic determinants shared across common GGE syndromes, but also suggest that heterogeneous configurations of genetic risk factors specify the phenotypic expression of absence and myoclonic seizures (Berkovic et al., 1987; Beck-Mannagetta & Janz, 1991; Berkovic et al., 1988; Schmitz et al., 2000; Winawer et al., 2003; Marini et al., 2004; Winawar et al., 2005; Kinirons et al., 2008).
Linkage mapping and positional candidate gene analysis provide a suitable approach to identify major susceptibility genes in families showing a clustering of GGE syndromes. Most of the currently known genes for rare monogenic forms of genetic epilepsies encode voltage-gated or ligand-gated ion channels (e.g., SCN1A, GABRA1, KCNQ2, and CHRNA4) (Reid et al., 2009; Poduri & Lowenstein, 2011). Although the known epilepsy genes identified in rare monogenic forms of epilepsy explain only a small proportion of the genetic liability, the casual gene mutations have allowed important insights into key mechanisms of epileptogenesis (Noebels, 2003; Reid et al., 2009). However, none of these epilepsy genes seems to play a substantial role in the genetic predisposition of common GGE syndromes.
Most of the linkage claims reported in genetically complex GGE syndromes (2q34-q36, 3p23-p14, 3q26, 5p15, 5q22, 6p12, 6p23.1, 7q14, 8p12, 8q24, 11q13, 13q31, 14q23, 15q14, 18q21, 19q13) remain controversial, because replication studies have often failed to confirm initial linkage hints in independent sets of families (Greenberg et al., 1988; Zara et al., 1995; Liu et al., 1996; Elmslie et al., 1997; Fong et al., 1998; Greenberg et al., 2000; Sander et al., 2000; Durner et al., 2001; Tauer et al., 2005; Hempelmann et al., 2006; Chioza et al., 2009; Greenberg & Subaran, 2011). The failure to detect replicable susceptibility genes for common epilepsies most likely reflects the underestimated degree of genetic complexity and heterogeneity in human epilepsies. With regard to the drastic loss of power of a linkage scan by the extent of locus heterogeneity, >300 families would be necessary to achieve a reasonable power to map a genetic risk factor, which is present in at least 30% of the families (Table S5). Given that most of the published linkage studies on common GGE syndromes included relatively small samples of <100 GGE-multiplex families, these studies provided low power to detect a major susceptibility locus when <50% of the families were linked to the same locus. Therefore, it is not surprising that the linkage studies reported so far did not reveal replicable susceptibility loci.
To achieve adequate power, the present genome-wide linkage analysis combined three linkage datasets, including 379 clinically well-characterized GGE-multiplex families of European ancestry. Our linkage meta-analysis aimed: (1) to map susceptibility loci shared by a broad spectrum of common GGEs and (2) to dissect out seizure type–related susceptibility genes contributing to the familial clustering of the same seizure type in familial GGEs.