Genome-wide association meta-analyses of drug-resistant epilepsy
Costin Leu, Andreja Avberšek, Remi Stevelink, Helena Martins Custodio, Siwei Chen, Doug Speed, Caitlin A. Bennett, Lina Jönsson, Unnur Unnsteinsdóttir, Andrea Jorgensen, Gianpiero L. Cavalleri, Norman Delanty, John Craig, Chantal Depondt, Michael R. Johnson, Bobby P.C. Koeleman, Emadeldin Hassanin, Maryam Omidvar, Roland Krause, Holger Lerche, Anthony G Marson, Terence J. O’Brien, Josemir W. Sander, Graeme J. Sills, Pasquale Striano, Federico Zara, Hreinn Stefánsson, Kari Stefansson, Patrick May, Benjamin M. Neale, Dennis Lal, Samuel F. Berkovic, Elisabetta Amadori, Danielle M. Andrade, Grazia Annesi, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen Barboza, Tobias H. Baumgartner, Betül Baykan, Nerses Bebek, Felicitas Becker, Caitlin A. Bennett, Samuel F. Berkovic, Ahmad Beydoun, Francesca Bisulli, Ingo Borggräfe, Christian Bosselmann, Robyn M. Busch, Laura Canafoglia, Barbara Castellotti, I-Jun Chou, Seo-Kyung Chung, Chris Cotsapas, Orrin Devinsky, Dennis J. Dlugos, Viola Doccini, Colin P. Doherty, Colin A. Ellis, Hany El-Naggar, Meghan Evans, Thomas N. Ferraro, Mark Fitzgerald, Francesco Fortunato, Jacqueline A. French, Elena Freri, Monica Gagliardi, Antonio Gambardella, Alica Goldman, Tiziana Granata, Namrata Gupta, Kevin Haas, Shinichi Hirose, Olivia Hoeper, Po-Chen Hung, Michael R. Johnson, Nathalie Khoueiry-Zgheib, Jean Khoury, Karl Martin Klein, Susanne Knake, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Wolfram S. Kunz, Ruben I. Kuzniecky, Patrick Kwan, Angelo Labate, Austin Lacey, Dennis Lal, Stephan Lauxmann, Charlotte Lawthom, Holger Lerche, Costin Leu, David Lewis-Smith, Calwing Liao, Chih-Hsiang Lin, Kuang-Lin Lin, Tarja Linnankivi, Daniel H. Lowenstein
Abstract
BACKGROUND: Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown. METHODS: We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: acquired or non-acquired focal and genetic generalized epilepsy. FINDINGS: , OR[C] = 0·74). This locus was not associated with any epilepsy subtype in the latest epilepsy GWAS (lowest uncorrected P = 0·009 for FE vs. healthy controls), and drug resistance in FE was not genetically correlated with susceptibility to FE itself. Seven genome-wide significant SNPs within this locus, encompassing the genes CNIH4, WDR26, and CNIH3, were identified to protect against drug-resistant FE. Further transcriptome-wide association studies (TWAS) imply significantly higher expression levels of CNIH3 and WDR26 in drug-resistant FE than in drug-responsive FE. CNIH3 is implicated in AMPA receptor assembly and function, while WDR26 haploinsufficiency is linked to intellectual disability and seizures. These findings suggest that CNIH3 and WDR26 may play a role in mediating drug response in focal epilepsy. INTERPRETATION: We identified a contribution of common genetic variation to drug-resistant focal epilepsy. These findings provide insights into possible mechanisms underlying drug response variability in epilepsy, offering potential targets for personalised treatment approaches. FUNDING: This work is part of the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI).