Genome-Wide Association Study Reveals Common Genetic Variants in Partial Epilepsy Susceptibility

Abstract

Partial epilepsies demonstrate significant heritability, yet specific genetic causes remain largely unidentified. While genome-wide association studies have successfully identified common variants linked to disease risk across numerous conditions, their role in partial epilepsies hasn't been thoroughly explored in well-powered research. We conducted a genome-wide association study examining common variants influencing risk across partial epilepsy syndromes, analyzing 3447 patients and 6939 controls of European ancestry. No genome-wide significant associations emerged, though several single nucleotide polymorphisms merit further investigation. Our findings exclude common genetic variants with effect sizes exceeding a modest 1.3 odds ratio as contributors to genetic susceptibility shared across partial epilepsies. This suggests common genetic variation plays, at most, a limited role in predisposition to partial epilepsies when examined across syndromes in European populations. The genetic architecture underlying partial epilepsy appears highly complex, reflecting substantial genotypic and phenotypic heterogeneity. Future research requires larger meta-analyses to identify variants with smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Additionally, our results indicate research should focus on identifying multiple rare variants likely responsible for at least some partial epilepsy heritability. Insights from genome-wide association studies will prove valuable for interpreting the extensive genetic variation emerging from whole-genome sequencing research.

Introduction

Epilepsy represents the most prevalent serious chronic neurological disorder, affecting 3–16 per 1000 individuals worldwide (Begley et al., 2007). Mendelian forms likely constitute only ∼1% of cases. The vast majority—termed 'sporadic' epilepsies—are considered 'complex': both genetic variation and environmental factors contribute variably across patients. Heritability estimates for partial epilepsy range considerably between studies, with some reaching 70% (Kjeldsen et al., 2001). All published twin and family studies demonstrate higher concordance in monozygotic versus dizygotic twins and substantial familial aggregation (e.g. Berkovic et al., 1998; Miller et al., 1998; Hemminki et al., 2006). Despite clear evidence for genetic contribution, the specific factors remain elusive. Numerous candidate gene investigations have failed to identify conclusive associations (see Discussion section in Tan et al., 2004; Cavalleri et al., 2005, 2007). These unsuccessful attempts at detecting robust associations typically reflect inadequate sample sizes yielding insufficient statistical power, and potentially misguided candidate gene selection. Many investigations focused on candidates derived from familial epilepsy genetics, particularly ion-channel genes, which comprise two-thirds of genes implicated in Mendelian epilepsies. Notably, among single-gene mutant mice exhibiting spontaneous or readily-evoked seizures, only approximately one-quarter of mutated genes encode ion channels (Frankel, 2009), suggesting a much broader spectrum of epilepsy-related pathways than currently recognized.

Despite partial epilepsy syndrome heterogeneity, certain shared biological features—including seizure components, secondary generalization of partial seizures, common EEG abnormalities, and fundamental biophysical and neurochemical cellular mechanisms like action potentials and synaptic transmission—suggest common susceptibility mechanisms exist. Research indicates different epilepsy types can cluster in families (Ottman et al., 1998; Bianchi et al., 2003; Berkovic et al., 2004), suggesting shared genetic factors increase susceptibility across epilepsy types. Recent microdeletion analyses have revealed apparently identical genetic defects contributing to different epilepsy forms (de Kovel et al., 2009), including 'symptomatic' epilepsies (Heinzen et al., 2010). Therefore, shared genetic variants may predispose to partial epilepsies regardless of syndrome type or structural cause. Identifying such variants would significantly enhance our understanding of partial epilepsy biology and potentially reveal targets for novel therapeutic interventions effective across partial epilepsy syndromes. Conversely, if well-powered comprehensive studies cannot detect common genetic variants influencing partial epilepsy susceptibility, our understanding of partial epilepsy genetic architecture must evolve, potentially necessitating alternative research approaches.

Here, we present findings from a genome-wide association study of partial epilepsies in a large European ancestry cohort. Our results indicate common variants are unlikely to exert clinically meaningful effects on predisposition to partial epilepsies shared across different syndromes.

Patients

We recruited individuals with partial epilepsy across seven countries (Supplementary material) during routine clinical visits. Diagnosis of partial epilepsy was established and/or confirmed by consultant epileptologists participating in this research, with comprehensive access to clinical histories and relevant investigation outcomes. We employed the International League Against Epilepsy definition (Commission on Classification and Terminology of the International League Against Epilepsy, 1989) for partial epilepsy throughout our study. Patients were classified as having epilepsy if they had experienced two or more unprovoked epileptic seizures. We defined partial epilepsy specifically as epilepsy characterized by seizures whose semiology or investigation (ictal EEG) demonstrated focal seizure origin. Our recruitment approach did not select patients based on specific epilepsy syndromes beyond the partial epilepsy classification, nor did we select based on presence or type of known structural abnormalities. Table 1 presents detailed phenotypic characteristics of patients within each country's cohort, utilizing a classification framework adapted from The International League Against Epilepsy's revised organization of epilepsy phenotypes (Berg et al., 2010). This systematic approach allowed comprehensive analysis of genetic variation potentially underlying susceptibility to various forms of partial epilepsy across demographically diverse populations.

Controls and Genotyping

Controls

Our control cohorts comprised (Supplementary Fig. 1): (i) 288 neurologically-normal Finnish controls and 285 Swiss controls without neurological conditions, specifically recruited and genotyped for this genetic variation study; (ii) 1165 USA controls from the Duke Memory study (Need et al., 2009; Cirulli et al., 2010), who provided consent for participation in epilepsy genetics research; 84% completed questionnaires regarding neurological history, with those reporting seizure history excluded; (iii) 5667 population controls from the Wellcome Trust Case Control Consortium (2007) Phase 2, September 2009 data release; (iv) 469 Finnish population controls, all aged 85 years or older at recruitment (Vantaa85+) (Myllykangas et al., 2005; Peuralinna et al., 2008); and (v) 211 neurologically-normal Irish controls from the Study of Irish Amyotrophic Lateral Sclerosis (Cronin et al., 2008).

Genotyping and quality control

We extracted DNA from blood samples using standardized procedures. All partial epilepsy patients and the Switzerland, Finland and USA controls underwent genotyping at Duke University. The majority of in-house genotyped patients (93.4%) and controls (77.4%) were processed using Human610-Quadv1 genotyping chips (Table 2). Genotype calling and comprehensive quality control were performed using Beadstudio v3 software following previously established protocols (Fellay et al., 2007), detailed further in the Supplementary material. Finnish control data from the Vantaa85+ study were received as Beadstudio files and processed using identical methodological approaches to ensure consistency across our epilepsy genetic variation analysis

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