Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families

Abstract

Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.

Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.

Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, p_adj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (p_adj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (p_adj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.

Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.

Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Keywords: Epilepsy genetics; Familial epilepsies; GABRG2; GEFS+; Genetic modifiers; Polygenic risk.

Fig. 1

a: Normalised distributions of epilepsy PRS in GEFS+ cohort stratified by epilepsy status, b: Mean epilepsy PRS values with 95% confidence intervals for cohort stratified by epilepsy status relative to the control population sample (bold horizontal line at y = 0). Note, the unaffected relative group without epilepsy includes individuals with no seizures and those with febrile seizures only. The epilepsy PRS model was comprised of 39,074 SNPs. The logistic mixed-effects regression model used PRS as exposure variable, sex assigned at birth, cohort, RV, FS and the first five ancestry PCs as fixed-effects covariates, and family identifier as random-effects covariate. The reported p-value was adjusted for the four PRS models tested (see methods; Supplementary Table S1).

Fig. 2

Mean epilepsy PRS difference with 95% confidence intervals between pairs of relatives within GEFS+ families. a: Comparison between relative pairs with concordant versus discordant phenotypes. b: Comparison between relative pairs grouped by degree of phenotype discordance where 0-grade difference captures concordant phenotypes. Statistical comparisons were made using linear mixed models with kinship included as a fixed-effect covariate and family identifier (FID) as a random-effects covariate. Permutation derived p-values were adjusted for five test comparisons.

Fig. 3

Pedigree of family with the GABRG2 p.Arg82Gln rare variant. Modified from version published in Marini et al., 2003 to only include relatives with both the RV and DNA available for PRS generation. Individual pedigree identifiers have been kept the same for all relatives that are included in both papers. Eight of the eleven relatives coded as severity scale 4 (orange symbol) have childhood absence epilepsy (a generalised epilepsy syndrome). The exceptions are individuals II-6 and IV-9 with temporal lobe epilepsy (a focal epilepsy syndrome) and III-15 with unclassified epilepsy. Individual II-2 coded as severity scale 5 (red symbol) has a diagnosis of epilepsy with myoclonic-atonic seizures (EMAtS).