Heritability of Magnetoencephalography Phenotypes Among Patients With Genetic Generalized Epilepsy and Their Siblings

Abstract

Objective: To assess whether neuronal signals in patients with genetic generalized epilepsy (GGE) are heritable, we examined magnetoencephalography resting-state recordings in patients and their healthy siblings.

Methods: In a prospective, cross-sectional design, we investigated source-reconstructed power and functional connectivity in patients, siblings, and controls. We analyzed 5 minutes of cleaned and awake data without epileptiform discharges in 6 frequency bands (1-40 Hz). We further calculated intraclass correlations to estimate heritability for the imaging patterns within families.

Results: Compared with controls (n = 45), patients with GGE (n = 25) showed widespread increased functional connectivity (θ to γ frequency bands) and power (δ to γ frequency bands) across the spectrum. Siblings (n = 18) fell between the levels of patients and controls. Heritability of the imaging metrics was observed in regions where patients strongly differed from controls, mainly in β frequencies, but also for δ and θ power. Network connectivity in GGE was heritable in frontal, central, and inferior parietal brain areas and power in central, temporo-parietal, and subcortical structures. Presence of generalized spike-wave activity during recordings and medication were associated with the network patterns, whereas other clinical factors such as age at onset, disease duration, or seizure control were not.

Conclusion: Metrics of brain oscillations are well suited to characterize GGE and likely relate to genetic factors rather than the active disease or treatment. High power and connectivity levels co-segregated in patients with GGE and healthy siblings, predominantly in the β band, representing an endophenotype of GGE.

Figure 1. Connectivity Within Families Related to Genetic Generalized Epilepsy (GGE) Imaging Patterns

(A) Individual global connectivity values of patients with GGE and siblings are plotted with regard to their family membership (columns of data within frequency bands). Data of patients with GGE without a corresponding sibling are not shown. GGE syndromes of patients in each family are indicated on the x-axis. Childhood absence epilepsy and juvenile absence epilepsy are referred to absence epilepsies (AE). (B) Color-coded heritability estimates (intraclass correlation [ICC] values) per region based on the Desikan-Kiliany atlas with small to large group-level differences between patients with GGE and controls (Cohen d > 0.2). Only ICC maps with a positive and significant correlation with averaged effect sizes are shown (p < 0.05). The color coding indicates the strength of ICC values in those regions for connectivity differences. ICC estimates were derived from random effect components of mixed models for each region, taking group and age effects into account. A large ICC indicates correlated imaging patterns for patient–sibling pairs in a family (n = 14) and thus heritability of the metrics. Cortical regions are displayed in the left column and subcortical regions are shown separately in the right column of the plot. GTCS = generalized tonic-clonic seizures; JME = juvenile myoclonic epilepsy.

Figure 2. Power Within Families Related to Genetic Generalized Epilepsy (GGE) Imaging Patterns

(A) Individual global power values of patients with GGE and siblings are plotted with regard to their family membership (columns of data within frequency bands). Data of patients with GGE without a corresponding sibling are not shown. GGE syndromes of patients in each family are indicated on the x-axis. Childhood absence epilepsy and juvenile absence epilepsy are referred to absence epilepsies (AE). For visualization purposes, power data were log10-transformed. (B) Color-coded heritability estimates (intraclass correlation [ICC] values) per region based on the Desikan-Kiliany atlas with small to large group-level differences between patients with GGE and controls (Cohen d > 0.2). Only ICC maps with a positive and significant correlation with averaged effect sizes are shown (p < 0.05). The color coding indicates the strength of ICC values in those regions for power differences. ICC estimates were derived from random effect components of mixed models for each region, taking group and age effects into account. A large ICC indicates correlated imaging patterns for patient–sibling pairs in a family (n = 14) and thus heritability of the metrics. Cortical regions are displayed in the left column and subcortical regions are shown separately in the right column of the plot. GTCS = generalized tonic-clonic seizures; JME = juvenile myoclonic epilepsy.

Figure 3. Group-Level Connectivity Differences

(A) Violin plots show individual data points, the density of the data, group means, and standard errors of the means for the global imaginary part of coherency in each frequency band (controls, n = 45; siblings, n = 18; patients with genetic generalized epilepsy [GGE], n = 25). Asterisks denote statistical significance at *p < 0.05 and **p < 0.001 for permutation-based group comparisons. (B) The plot highlights vertices with significantly higher connectivity values in patients with GGE (n = 25) than in controls (n = 45) and (C) higher connectivity values in patients with GGE (n = 25) than in siblings (n = 18). The color scale indicates –log10 p with a cutoff of 1.3 (corresponding to p < 0.05, familywise error corrected). In all analyses, age was included as covariate of no interest.

Figure 4. Group-Level Power Differences

(A) Violin plots show individual data points, the density of the data, group means, and standard errors of the means for global power in each frequency band (controls, n = 45; siblings, n = 18; patients with genetic generalized epilepsy [GGE], n = 25). Asterisks denote statistical significance at *p < 0.05 and **p < 0.001 for permutation-based group comparisons. For visualization purposes, power data were log10-transformed. (B) The plot highlights cortical and subcortical vertices with significantly higher power values in patients with GGE (n = 25) than in controls (n = 45). (C) The plot shows vertices with significantly higher power values in patients with GGE (n = 25) than in siblings (n = 18). The color scale indicates −log10 p with a cutoff of 1.3 (corresponding to p < 0.05, familywise error corrected). In all analyses, age was included as covariate of no interest.

Figure 5. Clinical Variables and Imaging Metrics

Vertex plots highlight cortical vertices with higher (A) connectivity and (B) power values in patients with genetic generalized epilepsy (GGE) with generalized spike-wave discharges (GSWD) (n = 9) than patients without GSWD (n = 16) during the magnetoencephalography recordings. These effects were present after exclusion of trials containing GSWD ±10 seconds of data and corrected for age effects. (C) The plot shows significantly lower connectivity in patients with GGE taking 2 or more antiepileptic drugs (n = 6) than patients taking fewer than 2 drugs (n = 19) at the study date. Age and presence of GSWD was included as covariate of no interest. Color scales indicate –log10 p with a cutoff of 1.3 (corresponding to p < 0.05, familywise error corrected).