학술논문
Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Document Type
Author abstract
Author
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; Krause, Roland; May, Patrick; Weckhuysen, Sarah; Petrovski, Slave; Kamalakaran, Sitharthan; Sisodiya, Sanjay M.; Cossette, Patrick; Cotsapas, Chris; De Jonghe, 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.; Sterbova, Katalin; Vlckova, Marketa; Sedlackova, Lucie; Lassuthova, Petra; Klein, Karl Martin; Rosenow, Felix; Reif, Philipp S.; Knake, Susanne; Kunz, Wolfram S.; Zsurka, Gabor; Elger, Christian E.; Bauer, Jurgen; Rademacher, Michael; Pendziwiat, Manuela; Muhle, Hiltrud; Rademacher, Annika; van Baalen, Andreas; von Spiczak, Sarah; Stephani, Ulrich; Afawi, Zaid; Korczyn, Amos D.; Kanaan, Moien; Canavati, Christina; Kurlemann, Gerhard; Muller-Schluter, Karen; Kluger, Gerhard; Hausler, 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; Borggrafe, Ingo; Schankin, Christoph J.; Mayer, Thomas; Korinthenberg, Rudolf; Brockmann, Knut; Dennig, Dieter; Madeleyn, Rene; Kalviainen, 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.; Barisic, 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; Tumiene, Birute; Sadleir, Lynette G.; King, Chontelle; Mountier, Emily; Caglayan, S. Hande; Arslan, Mutluay; Yapici, Zuhal; Yis, Uluc; Topaloglu, Pinar; Kara, Bulent; Turkdogan, Dilsad; Gundogdu-Eken, Asli; Bebek, Nerses; Ugur-Iseri, Sibel; Baykan, Betul; Salman, Baris; Haryanyan, Garen; Yucesan, Emrah; Kesim, Yesim; Ozkara, Cigdem; 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.; Fanous, Ayman H.; McCarroll, Steven A.; Gupta, Namrata; Gabriel, Stacey B.; Daly, Mark J.; Lander, Eric S.; Lowenstein, Daniel H.; Goldstein, David B.; Lerche, Holger; Berkovic, Samuel F.; Neale, Benjamin M.
Source
American Journal of Human Genetics. August 1, 2019, Vol. 105 Issue 2, 267
Subject
Language
English
ISSN
0002-9297
Abstract
Epi25 Collaborative (*) Keywords epilepsy; seizures; epileptic encephalopathy; exome; sequencing; burden analysis Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA.sub.A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology. * Corresponding author Article History: Received 18 January 2019; Accepted 29 May 2019 (miscellaneous) Published: July 18, 2019 Byline: Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slave Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Sterbova, Marketa Vlckova, Lucie Sedlackova, Petra Lassuthova, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gabor Zsurka, Christian E. Elger, Jurgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Muller-Schluter, Gerhard Kluger, Martin Hausler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggrafe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Gerhard Kurlemann, Dieter Dennig, Rene Madeleyn, Reetta Kalviainen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barisic, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapici, Uluc Yis, Pinar Topaloglu, Bulent Kara, Dilsad Turkdogan, Asli Gundogdu-Eken, Nerses Bebek, Sibel Ugur-Iseri, Betul Baykan, Baris Salman, Garen Haryanyan, Emrah Yucesan, Yesim Kesim, Cigdem Ozkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale