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

• Type of Material: Article
• Authors: Karen L Oliver, University of Melbourne; Colin A Ellis, The Children's Hospital of Philadelphia; Ingrid E Scheffer, University of Melbourne; Shiva Ganesan, The Children's Hospital of Philadelphia; Costin Leu, Cleveland Clinic Foundation; Lynette G Sadleir, University of Otago; Erin L Heinzen, UNC Eshelman School of Pharmacy; Heather C Mefford, St. Jude Children's Research Hospital; Andrew J Bass, Emory University School of Medicine; Sarah W Curtis, Emory University School of Medicine; Rebekah V Harris, University of Melbourne; David C Whiteman, QIMR Berghofer Medical Research Institute; Ingo Helbig, The Children's Hospital of Philadelphia; Ruth Ottman, Gertrude H. Sergievsky Center; Michael Epstein, Emory University; Melanie Bahlo, Walter and Eliza Hall Institute of Medical Research; Samuel F Berkovic, University of Melbourne
• Language: English
• Date: 2022-07-01
• Publisher: Elsevier B.V.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2022.104079
• Title of Journal or Parent Work: eBioMedicine
• Volume: 81
• Start Page: 104079
• End Page: 104079
• Grant/Funding Information: The QSKIN Study is supported by Grants [APP1185416, APP1073898, APP1063061] from the NHMRC. This work was also supported by the Victorian Government's Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS).; Colin A Ellis is supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health Award Number K23NS121520; by the American Academy of Neurology Susan S Spencer Clinical Research Training Scholarship; by the Thomas B and Jeannette E Laws McCabe Fund at the University of Pennsylvania; and by the Mirowski Family Foundation. Ingrid Scheffer and Samuel Berkovic are supported by a National Health and Medical Research Council (NHMRC) of Australia Program Grant [1091593], and Ingrid Scheffer is further supported by a NHMRC Practitioner Fellowship [1006110] and Senior Investigator grant [1172897], the Medical Research Future Fund, Australian Epilepsy Research Fund, Shenzhen Sanming Development Grant, Einstein Foundation Berlin and the Health Research Council of New Zealand.; Melanie Bahlo is supported by an NHMRC Investigator grant [APP1195236]. David Whiteman is supported by a Research Fellowship [APP1155413] from the NHMRC. Samuel Berkovic and Heather Mefford are supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health.; Genomic data for participants from tertiary hospitals in the AUS, NZ, and the US that contributed to this study were provided by the Epi25 Collaborative (www.epi-25.org).; Lynette Sadleir is supported by the Health Research Council of New Zealand and Cure Kids New Zealand. Ingo Helbig is supported by the German Research Foundation (HE5415/6-1, DFG/FNR INTER Research Unit FOR2715 HE5415/7-1 and HE5415/7-2); The Hartwell Foundation; The National Institute for Neurological Disorders and Stroke (K02 NS112600); The Center Without Walls on the Ion channel function in Epilepsy (U54 NS108874); Through the Intellectual and Developmental Disabilities Research Center (IDDRC); The University of Pennsylvania (U54 HD086984); The National Center for Advancing Translational Sciences of the National Institutes of Health (Award Number UL1TR001878); The Institute for Translational Medicine Therapeutics’ Transdisciplinary Program (ITMAT); The Epilepsy NeuroGenetics Initiative (ENGIN); EuroEpinomics-Rare Epilepsy Syndrome (RES); The International League Against Epilepsy (ILAE).; Karen L Oliver is supported by an Australian Government Research Training Program Scholarship [APP533086] provided by the Australian Commonwealth Government and the University of Melbourne.
• Keywords: Polygenic risk scores; Genome-Wide Association Study; Epilepsy, Generalized; Common genetic variation; Familial epilepsies; Multifactorial Inheritance; Humans; Epilepsy genetics; Epilepsy; Epileptic Syndromes; Genetic Predisposition to Disease
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health

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, padj = 5×10−9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 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 (padj = 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.