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

doi:10.1016/j.ebiom.2022.104079

. 2022 Jul:81:104079.

doi: 10.1016/j.ebiom.2022.104079. Epub 2022 May 27.

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

Karen L Oliver¹, Colin A Ellis², Ingrid E Scheffer³, Shiva Ganesan⁴, Costin Leu⁵, Lynette G Sadleir⁶, Erin L Heinzen⁷, Heather C Mefford⁸, Andrew J Bass⁹, Sarah W Curtis⁹, Rebekah V Harris¹⁰; Epi4K Consortium; David C Whiteman¹¹, Ingo Helbig⁴, Ruth Ottman¹², Michael P Epstein⁹, Melanie Bahlo¹³, Samuel F Berkovic¹⁴

Affiliations

¹ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia; Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia.
² The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, VIC, Australia; The Florey Institute and Murdoch Children's Research Institute, VIC, Australia.
⁴ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA 02142, USA.
⁶ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
⁷ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁸ Center for Pediatric Neurological Disease Research, St Jude Children's Research Hospital, Memphis, TN, USA.
⁹ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia.
¹¹ Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹² Departments of Epidemiology and Neurology, and the Sergievsky Center, Columbia University, New York, NY, USA; Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
¹³ Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁴ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia. Electronic address: [email protected].

PMID: 35636315
PMCID: PMC9156876
DOI: 10.1016/j.ebiom.2022.104079

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

Karen L Oliver et al. EBioMedicine. 2022 Jul.

. 2022 Jul:81:104079.

doi: 10.1016/j.ebiom.2022.104079. Epub 2022 May 27.

Authors

Affiliations

¹ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia; Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia.
² The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, VIC, Australia; The Florey Institute and Murdoch Children's Research Institute, VIC, Australia.
⁴ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA 02142, USA.
⁶ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
⁷ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁸ Center for Pediatric Neurological Disease Research, St Jude Children's Research Hospital, Memphis, TN, USA.
⁹ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia.
¹¹ Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹² Departments of Epidemiology and Neurology, and the Sergievsky Center, Columbia University, New York, NY, USA; Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
¹³ Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁴ Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia. Electronic address: [email protected].

PMID: 35636315
PMCID: PMC9156876
DOI: 10.1016/j.ebiom.2022.104079

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.

Keywords: Common genetic variation; Epilepsy genetics; Familial epilepsies; Polygenic risk scores.

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Conflict of interest statement

Declaration of interests Samuel Berkovic has received grants from UCB Pharma, Eisai, SciGen; consulting fees from Praxis Precision Medicines, Sequiris; honoraria from Eisai; has a patent for SCN1A testing held by Bionomics Inc licensed to Athena Diagnostics and Genetics Technologies Ltd. Ingrid Scheffer has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Knopp Biosciences and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Xenon Pharmaceuticals, Anavex Life Sciences, Ovid Therapeutics, Epigenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium and UCB; and is a Non-Executive Director of Bellberry Ltd. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). David Whiteman has received speaker fees from Pierre Fabre. Melanie Bahlo has received payment for thesis examination from University of Melbourne, University of Sydney, University of Western Australia; has received support for attending conferences: Genemappers, International Conference on Familial Cortical Myoclonic Tremor Epilepsy and Repeat Expansion Diseases, Lorne Genome, Bioinforsummer, Australian Academy of Science Australia-China symposium on precision medicine; has served as an advisor for ALADIN, Kinghorn Sequencing Center, Murdoch Children's Research Institute, Viertel Foundation; is a committee member for Australian Academy of Health and Medical Sciences, American Epilepsy Society Basic Sciences, Gen V Bioresource Genetics. Costin Leu received conference travel support from the International Epilepsy Congress/ILAE. Ingo Helbig received travel support from the Americal Epilepsy Society. Heather Mefford has received support from CURE Epilepsy and sits on the American Society of Human Genetics Board of Directors. Lynette Sadleir has received consulting fees from the Epilepsy Consortium, Zynerba; is an advisor to Eisai; and is treasurer for the New Zealand League Against Epilepsy.

Figures

**Figure 1**
**Epilepsy polygenic risk is enriched in familial cases**. Polygenic risk scores (PRS) for all epilepsies were higher in patients with familial epilepsy than in population controls, sporadic epilepsy patients, and unaffected relatives of familial cases. (a) Normalised distributions of epilepsy PRS (b) Mean epilepsy PRS values. Logistic mixed-effects regression models used PRS as exposure variable, sex and the first five ancestry principal components as fixed-effects covariates, and genetic relatedness matrix as random-effects covariate. P-values from Wald tests were corrected for multiple comparisons. ns P_adj ≥ 0.05, * P_adj ≤ 0.05, ** P_adj ≤ 0.01, *** P_adj ≤ 0.001, **** P_adj ≤ 0.0001. Abbreviations: PRS, polygenic risk score; CI, confidence interval.

**Figure 2**
**Familial epilepsy cases by decile of Epilepsy PRS**. Familial epilepsy cases were assigned to PRS deciles derived from the population control distribution. Odds ratios are the odds of being an affected case relative to the lowest decile (denoted by dashed grey line).

**Figure 3**
**Polygenic risk stratified by epilepsy type**. (a) The Epilepsy PRS model was highest in familial cases across all epilepsy phenotype groups. (b) The polygenic risk scores (PRS) model for risk of genetic generalised epilepsy (GGE) was highest in individuals with familial GGE. (c) The PRS model for risk of focal epilepsy was not different from controls in any of the phenotypic groups. Logistic mixed-effects regression models used PRS as exposure variable, sex and the first five ancestry principal components as fixed-effects covariates, and genetic relatedness matrix as random-effects covariate. Stars indicate statistically significant comparisons to the control group, corrected for multiple comparisons (* P_adj ≤ 0.05, ** P_adj ≤ 0.01, *** P_adj ≤ 0.001, **** P_adj ≤ 0.0001); all other comparisons were non-significant (P_adj > 0.05). Full results are available in Supplementary Table 7.

**Figure 4**
**PRS in familial cases carrying rare epilepsy variants no different to non-carriers**. Polygenic risk score (PRS) models specific to (a) all epilepsy, (b) genetic generalised epilepsies (GGE) and (c) focal epilepsies in individuals with familial epilepsy who had known rare pathogenic variants (red; n = 140) versus individuals without rare pathogenic variants (blue; n = 1,678). Statistical comparisons were non-significant (P_adj > 0.05). Full results are available in Supplementary Table 9.

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References

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[1] Annegers J.F., Hauser W.A., Anderson V.E., Kurland LT. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology. 1982;32:174–179. - PubMed

[2] Annegers J.F., Hauser W.A., Anderson V.E., Kurland LT. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology. 1982;32:174–179. - PubMed

[3] Lennox W.G. The heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:529–536. - PubMed

[4] Lennox W.G. The heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:529–536. - PubMed

[5] Steinlein O.K., Mulley J.C., Propping P., et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11:201–203. - PubMed

[6] Steinlein O.K., Mulley J.C., Propping P., et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11:201–203. - PubMed

[7] Perucca P., Bahlo M., Berkovic S.F. The genetics of epilepsy. Annu Rev Genom Hum Genet. 2020;21:205–230. - PubMed

[8] Perucca P., Bahlo M., Berkovic S.F. The genetics of epilepsy. Annu Rev Genom Hum Genet. 2020;21:205–230. - PubMed

[9] Guerrini R., Balestrini S., Wirrell E.C., Walker M.C. Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies. Neurology. 2021;97(17):817–831. - PMC - PubMed

[10] Guerrini R., Balestrini S., Wirrell E.C., Walker M.C. Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies. Neurology. 2021;97(17):817–831. - PMC - PubMed

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

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

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