Using common genetic variants to find drugs for common epilepsies
Nasir Mirza, Remi Stevelink, Basel A. Taweel, Bobby P.C. Koeleman, Anthony G Marson, Bassel Abou‐Khalil, Pauls Auce, Andreja Avberšek, Melanie Bahlo, David J. Balding, Thomas Bast, Larry Baum, Albert J. Becker, Felicitas Becker Bianca Berghuis, Samuel F. Berkovic, Katja Boysen, Jonathan P. Bradfield, Lawrence C. Brody, Russell J. Buono, Ellen Campbell, Gregory D. Cascino, Claudia B. Catarino, Gianpiero L. Cavalleri, Stacey S. Cherny, Krishna Chinthapalli, Alison J. Coffey, Alastair Compston, Antonietta Coppola, Patrick Cossette, John Craig, Gerrit‐Jan de Haan, Peter De Jonghe, Carolien G. F. de Kovel, Norman Delanty, Chantal Depondt, Orrin Devinsky, Dennis Dlugos, Colin P. Doherty, Christian E. Elger, Johan G. Eriksson, Thomas N. Ferraro, Martha Feucht, Ben Francis, André Franke, Jacqueline A. French, Saskia Freytag, Verena Gaus, Eric B. Geller, Christian Gieger, Tracy A. Glauser, Simon Glynn, David B. Goldstein, Hongsheng Gui, Youling Guo, Kevin F. Haas, Håkon Håkonarson, Kerstin Hallmann, Sheryl R. Haut, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Helle Hjalgrim, Michele Iacomino, Andrés Ingason, Jennifer Jamnadas-Khoda, Michael R. Johnson, Reetta Kälviäinen, Anne-Mari Kantanen, Dalia Kasperavičiūtė, Dorothée Kasteleijn‐Nolst Trenité, Heidi E. Kirsch, Robert C. Knowlton, Bobby P.C. Koeleman, Roland Krause, Martin Krenn, Wolfram S. Kunz, Ruben Kuzniecky, Patrick Kwan, Dennis Lal, YL Lau, Holger Lerche, Costin Leu, Wolfgang Lieb, Dick Lindhout, Warren Lo, Íscia Lopes‐Cendes, Daniel H. Lowenstein, Alberto Malovini, Anthony G Marson, Thomas Mayer, Mark McCormack, James L. Mills, Nasir Mirza, Martina Moerzinger, Rikke S. Møller, Anne M. Molloy, Hiltrud Muhle, Mark R. Newton, Ping-Wing Ng, Markus M. Nöthen
Abstract
Abstract Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs’ activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs’ effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins’ dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases.