Dataset Information

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

ABSTRACT:

Background

The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies.

Methods

Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry.

Findings

Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, p_adj = 5×10^-9), sporadic patients (OR 1·11, p_adj = 0.008), and their own unaffected relatives (OR 1·12, p_adj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (p_adj = 5×10^-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases.

Interpretation

The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology.

Funding

National Health and Medical Research Council of Australia, National Institutes of Health, American Academy of Neurology, Thomas B and Jeannette E Laws McCabe Fund, Mirowski Family Foundation.

SUBMITTER: Oliver KL

PROVIDER: S-EPMC9156876 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

Oliver Karen L KL Ellis Colin A CA Scheffer Ingrid E IE Ganesan Shiva S Leu Costin C Sadleir Lynette G LG Heinzen Erin L EL Mefford Heather C HC Bass Andrew J AJ Curtis Sarah W SW Harris Rebekah V RV Whiteman David C DC Helbig Ingo I Ottman Ruth R Epstein Michael P MP Bahlo Melanie M Berkovic Samuel F SF

EBioMedicine 20220527

<h4>Background</h4>The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies.<h4>Methods</h4>Using common variants derived from the largest epilepsy ...[more]

PMID: 35636315

Similar Datasets

Project description:BackgroundPhenotypic 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.MethodsWe 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.Findings304 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, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 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 (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.InterpretationWe 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.FundingNational Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Dataset Information

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

Background

Methods

Findings

Interpretation

Funding

Publications

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

Similar Datasets

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