Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery
Karen L. Oliver,
Colin A. Ellis,
Ingrid E. Scheffer,
Shiva Ganesan,
Costin Leu,
Lynette G. Sadleir,
Erin L. Heinzen,
Heather C. Mefford,
Andrew J. Bass,
Sarah W. Curtis,
Rebekah V. Harris,
David C. Whiteman,
Ingo Helbig,
Ruth Ottman,
Michael P. Epstein,
Melanie Bahlo,
Samuel F. Berkovic
Affiliations
Karen L. Oliver
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
Colin A. Ellis
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
Ingrid E. Scheffer
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
Shiva Ganesan
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
Costin Leu
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
Lynette G. Sadleir
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Erin L. Heinzen
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
Heather C. Mefford
Center for Pediatric Neurological Disease Research, St Jude Children's Research Hospital, Memphis, TN, USA
Andrew J. Bass
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Sarah W. Curtis
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Rebekah V. Harris
Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia
David C. Whiteman
Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Ingo Helbig
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
Ruth Ottman
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
Michael P. Epstein
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Melanie Bahlo
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
Samuel F. Berkovic
Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia; Corresponding author.
Summary: 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.
