Title Distinct gene-set burden patterns underlie common generalized and focal epilepsies /
Authors Koko, Mahmoud ; Krause, Roland ; Sander, Thomas ; Bobbili, Dheeraj Reddy ; Nothnagel, Michael ; May, Patrick ; Lerche, Holger ; Feng, Yen-Chen Anne ; Howrigan, Daniel P ; Abbott, Liam E ; Tashman, Katherine ; Cerrato, Felecia ; Singh, Tarjinder ; Heyne, Henrike ; Byrnes, Andrea ; Churchhouse, Claire ; Watts, Nick ; Solomonson, Matthew ; Lal, Dennis ; Heinzen, Erin L ; Dhindsa, Ryan S ; Stanley, Kate E ; Cavalleri, Gianpiero L ; Hakonarson, Hakon ; Helbig, Ingo ; Weckhuysen, Sarah ; Petrovski, Slavé ; Kamalakaran, Sitharthan ; Sisodiya, Sanjay M ; Cossette, Patrick ; Cotsapas, Chris ; DeJonghe, Peter ; Dixon-Salazar, Tracy ; Guerrini, Renzo ; Kwan, Patrick ; Marson, Anthony G ; Stewart, Randy ; Depondt, Chantal ; Dlugos, Dennis J ; Scheffer, Ingrid E ; Striano, Pasquale ; Freyer, Catharine ; McKenna, Kevin ; Regan, Brigid M ; Bellows, Susannah T ; Leu, Costin ; Bennett, Caitlin A ; Johns, Esther M C ; Macdonald, Alexandra ; Shilling, Hannah ; Burgess, Rosemary ; Weckhuysen, Dorien ; Bahlo, Melanie ; O'Brien, Terence J ; Todaro, Marian ; Stamberger, Hannah ; Andrade, Danielle M ; Sadoway, Tara R ; Mo, Kelly ; Krestel, Heinz ; Gallati, Sabina ; Papacostas, Savvas S ; Kousiappa, Ioanna ; Tanteles, George A ; Štěrbová, Katalin ; Vlčková, Markéta ; Sedláčková, Lucie ; Laššuthová, Petra ; Klein, Karl Martin ; Rosenow, Felix ; Reif, Philipp S ; Knake, Susanne ; Kunz, Wolfram S ; Zsurka, Gábor ; Elger, Christian E ; Bauer, Jürgen ; Rademacher, Michael ; Pendziwiat, Manuela ; Muhle, Hiltrud ; Rademacher, Annika ; vanBaalen, Andreas ; vonSpiczak, Sarah ; Stephani, Ulrich ; Afawi, Zaid ; Korczyn, Amos D ; Kanaan, Moien ; Canavati, Christina ; Kurlemann, Gerhard ; Müller-Schlüter, Karen ; Kluger, Gerhard ; Häusler, Martin ; Blatt, Ilan ; Lemke, Johannes R ; Krey, Ilona ; Weber, Yvonne G ; Wolking, Stefan ; Becker, Felicitas ; Hengsbach, Christian ; Rau, Sarah ; Maisch, Ana F ; Steinhoff, Bernhard J ; Schulze-Bonhage, Andreas ; Schubert-Bast, Susanne ; Schreiber, Herbert ; Borggräfe, Ingo ; Schankin, Christoph J ; Mayer, Thomas ; Korinthenberg, Rudolf ; Brockmann, Knut ; Dennig, Dieter ; Madeleyn, Rene ; Kälviäinen, Reetta ; Auvinen, Pia ; Saarela, Anni ; Linnankivi, Tarja ; Lehesjoki, Anna-Elina ; Rees, Mark I ; Chung, Seo-Kyung ; Pickrell, William O ; Powell, Robert ; Schneider, Natascha ; Balestrini, Simona ; Zagaglia, Sara ; Braatz, Vera ; Johnson, Michael R ; Auce, Pauls ; Sills, Graeme J ; Baum, Larry W ; Sham, Pak C ; Cherny, Stacey S ; Lui, Colin H T ; Barišić, Nina ; Delanty, Norman ; Doherty, Colin P ; Shukralla, Arif ; McCormack, Mark ; El-Naggar, Hany ; Canafoglia, Laura ; Franceschetti, Silvana ; Castellotti, Barbara ; Granata, Tiziana ; Zara, Federico ; Iacomino, Michele ; Madia, Francesca ; Vari, Maria Stella ; Mancardi, Maria Margherita ; Salpietro, Vincenzo ; Bisulli, Francesca ; Tinuper, Paolo ; Licchetta, Laura ; Pippucci, Tommaso ; Stipa, Carlotta ; Minardi, Raffaella ; Gambardella, Antonio ; Labate, Angelo ; Annesi, Grazia ; Manna, Lorella ; Gagliardi, Monica ; Parrini, Elena ; Mei, Davide ; Vetro, Annalisa ; Bianchini, Claudia ; Montomoli, Martino ; Doccini, Viola ; Marini, Carla ; Suzuki, Toshimitsu ; Inoue, Yushi ; Yamakawa, Kazuhiro ; Tumienė, Birutė ; Sadleir, Lynette G ; King, Chontelle ; Mountier, Emily ; Caglayan, Hande S ; Arslan, Mutluay ; Yapıcı, Zuhal ; Yis, Uluc ; Topaloglu, Pınar ; Kara, Bulent ; Turkdogan, Dilsad ; Gundogdu-Eken, Aslı ; Bebek, Nerses ; Uğur-İşeri, Sibel ; Baykan, Betül ; Salman, Barış ; Haryanyan, Garen ; Yücesan, Emrah ; Kesim, Yeşim ; Özkara, Çiğdem ; Poduri, Annapurna ; Shiedley, Beth R ; Shain, Catherine ; Buono, Russell J ; Ferraro, Thomas N ; Sperling, Michael R ; Lo, Warren ; Privitera, Michael ; French, Jacqueline A ; Schachter, Steven ; Kuzniecky, Ruben I ; Devinsky, Orrin ; Hegde, Manu ; Khankhanian, Pouya ; Helbig, Katherine L ; Ellis, Colin A ; Spalletta, Gianfranco ; Piras, Fabrizio ; Piras, Federica ; Gili, Tommaso ; Ciullo, Valentina ; Reif, Andreas ; McQuillin, Andrew ; Bass, Nick ; McIntosh, Andrew ; Blackwood, Douglas ; Johnstone, Mandy ; Palotie, Aarno ; Pato, Michele T ; Pato, Carlos N ; Bromet, Evelyn J ; Carvalho, Celia Barreto ; Achtyes, Eric D ; Azevedo, Maria Helena ; Kotov, Roman ; Lehrer, Douglas S ; Malaspina, Dolores ; Marder, Stephen R ; Medeiros, Helena ; Morley, Christopher P ; Perkins, Diana O ; Sobell, Janet L ; Buckley, Peter F ; Macciardi, Fabio ; Rapaport, Mark H ; Knowles, James A ; Cohort, Genomic Psychiatry ; Fanous, Ayman H ; McCarroll, Steven A ; Gupta, Namrata ; Gabriel, Stacey B ; Daly, Mark J ; Lander, Eric S ; Lowenstein, Daniel H ; Goldstein, David B ; Berkovic, Samuel F ; Neale, Benjamin M
DOI 10.1016/j.ebiom.2021.103588
Full Text Download
Is Part of eBioMedicine.. Amsterdam : Elsevier BV. 2021, vol. 72, art. no. 103588, p. [1-13].. ISSN 2352-3964. eISSN 2352-3964
Keywords [eng] Burden analysis ; Ultra-rare variants ; Gene-sets ; Epilepsy ; Exome sequencing
Abstract [eng] Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. Funding DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
Published Amsterdam : Elsevier BV
Type Journal article
Language English
Publication date 2021
CC license CC license description