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

Andrew J Bass, Samuel F Berkovic, Melanie Bahlo, Michael P Epstein, Ruth Ottman, Ingo Helbig, David C Whiteman, Rebekah V Harris, Sarah W Curtis, Karen L Oliver, Heather C Mefford, Erin L Heinzen, Lynette G Sadleir, Costin Leu, Shiva Ganesan, Ingrid E Scheffer, Colin A Ellis

Journal: EBioMedicine 2022;81():104079

PMID: 35636315

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

Address: 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.; 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.; 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.; 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.; 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.; Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.; 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.; Center for Pediatric Neurological Disease Research, St Jude Children's Research Hospital, Memphis, TN, USA.; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia.; Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.; 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.; 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.; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia. Electronic address: [email protected].

DOI: 10.1016/j.ebiom.2022.104079

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MeSH Terms: Epilepsy, Epilepsy, Generalized, Epileptic Syndromes, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance