Siwei Chen, Bassel W Abou-Khalil, Zaid Afawi, Quratulain Zulfiqar Ali, Elisabetta Amadori, Alison Anderson, Joe Anderson, Danielle M Andrade, Grazia Annesi, Mutluay Arslan, Pauls Auce, Melanie Bahlo, Mark D Baker, Ganna Balagura, Simona Balestrini, Eric Banks, Carmen Barba, Karen Barboza, Fabrice Bartolomei, Nick Bass, Larry W Baum, Tobias H Baumgartner, Betül Baykan, Nerses Bebek, Felicitas Becker, Caitlin A Bennett, Ahmad Beydoun, Claudia Bianchini, Francesca Bisulli, Douglas Blackwood, Ilan Blatt, Ingo Borggräfe, Christian Bosselmann, Vera Braatz, Harrison Brand, Knut Brockmann, Russell J Buono, Robyn M Busch, S Hande Caglayan, Laura Canafoglia, Christina Canavati, Barbara Castellotti, Gianpiero L Cavalleri, Felecia Cerrato, Francine Chassoux, Christina Cherian, Stacey S Cherny, Ching-Lung Cheung, I-Jun Chou, Seo-Kyung Chung, Claire Churchhouse, Valentina Ciullo, Peggy O Clark, Andrew J Cole, Mahgenn Cosico, Patrick Cossette, Chris Cotsapas, Caroline Cusick, Mark J Daly, Lea K Davis, Peter De Jonghe, Norman Delanty, Dieter Dennig, Chantal Depondt, Philippe Derambure, Orrin Devinsky, Lidia Di Vito, Faith Dickerson, Dennis J Dlugos, Viola Doccini, Colin P Doherty, Hany El-Naggar, Colin A Ellis, Leon Epstein, Meghan Evans, Annika Faucon, Yen-Chen Anne Feng, Lisa Ferguson, Thomas N Ferraro, Izabela Ferreira Da Silva, Lorenzo Ferri, Martha Feucht, Madeline C Fields, Mark Fitzgerald, Beata Fonferko-Shadrach, Francesco Fortunato, Silvana Franceschetti, Jacqueline A French, Elena Freri, Jack M Fu, Stacey Gabriel, Monica Gagliardi, Antonio Gambardella, Laura Gauthier, Tania Giangregorio, Tommaso Gili, Tracy A Glauser, Ethan Goldberg, Alica Goldman, David B Goldstein, Tiziana Granata, Riley Grant, David A Greenberg, Renzo Guerrini, Aslı Gundogdu-Eken, Namrata Gupta, Kevin Haas, Hakon Hakonarson, Garen Haryanyan, Martin Häusler, Manu Hegde, Erin L Heinzen, Ingo Helbig, Christian Hengsbach, Henrike Heyne, Shinichi Hirose, Edouard Hirsch, Chen-Jui Ho, Olivia Hoeper, Daniel P Howrigan, Donald Hucks, Po-Chen Hung, Michele Iacomino, Yushi Inoue, Luciana Midori Inuzuka, Atsushi Ishii, Lara Jehi, Michael R Johnson, Mandy Johnstone, Reetta Kälviäinen, Moien Kanaan, Bulent Kara, Symon M Kariuki, Josua Kegele, Yeşim Kesim, Nathalie Khoueiry-Zgheib, Jean Khoury, Chontelle King, Karl Martin Klein, Gerhard Kluger, Susanne Knake, Fernando Kok, Amos D Korczyn, Rudolf Korinthenberg, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Martin Krenn, Heinz Krestel, Ilona Krey, Wolfram S Kunz, Gerhard Kurlemann, Ruben I Kuzniecky, Patrick Kwan, Maite La Vega-Talbott, Angelo Labate, Austin Lacey, Dennis Lal, Petra Laššuthová, Stephan Lauxmann, Charlotte Lawthom, Stephanie L Leech, Anna-Elina Lehesjoki, Johannes R Lemke, Holger Lerche, Gaetan Lesca, Costin Leu, Naomi Lewin, David Lewis-Smith, Gloria Hoi-Yee Li, Calwing Liao, Laura Licchetta, Chih-Hsiang Lin, Kuang-Lin Lin, Tarja Linnankivi, Warren Lo, Daniel H Lowenstein, Chelsea Lowther, Laura Lubbers, Colin H T Lui, Lucia Inês Macedo-Souza, Rene Madeleyn, Francesca Madia, Stefania Magri, Louis Maillard, Lara Marcuse, Paula Marques, Anthony G Marson, Abigail G Matthews, Patrick May, Thomas Mayer, Wendy McArdle, Steven M McCarroll, Patricia McGoldrick, Christopher M McGraw, Andrew McIntosh, Andrew McQuillan, Kimford J Meador, Davide Mei, Véronique Michel, John J Millichap, Raffaella Minardi, Martino Montomoli, Barbara Mostacci, Lorenzo Muccioli, Hiltrud Muhle, Karen Müller-Schlüter, Imad M Najm, Wassim Nasreddine, Samuel Neaves, Bernd A Neubauer, Charles R J C Newton, Jeffrey L Noebels, Kate Northstone, Sam Novod, Terence J O'Brien, Seth Owusu-Agyei, Çiğdem Özkara, Aarno Palotie, Savvas S Papacostas, Elena Parrini, Carlos Pato, Michele Pato, Manuela Pendziwiat, Page B Pennell, Slavé Petrovski, William O Pickrell, Rebecca Pinsky, Dalila Pinto, Tommaso Pippucci, Fabrizio Piras, Federica Piras, Annapurna Poduri, Federica Pondrelli, Danielle Posthuma, Robert H W Powell, Michael Privitera, Annika Rademacher, Francesca Ragona, Byron Ramirez-Hamouz, Sarah Rau, Hillary R Raynes, Mark I Rees, Brigid M Regan, Andreas Reif, Eva Reinthaler, Sylvain Rheims, Susan M Ring, Antonella Riva, Enrique Rojas, Felix Rosenow, Philippe Ryvlin, Anni Saarela, Lynette G Sadleir, Barış Salman, Andrea Salmon, Vincenzo Salpietro, Ilaria Sammarra, Marcello Scala, Steven Schachter, André Schaller, Christoph J Schankin, Ingrid E Scheffer, Natascha Schneider, Susanne Schubert-Bast, Andreas Schulze-Bonhage, Paolo Scudieri, Lucie Sedláčková, Catherine Shain, Pak C Sham, Beth R Shiedley, S Anthony Siena, Graeme J Sills, Sanjay M Sisodiya, Jordan W Smoller, Matthew Solomonson, Gianfranco Spalletta, Kathryn R Sparks, Michael R Sperling, Hannah Stamberger, Bernhard J Steinhoff, Ulrich Stephani, Katalin Štěrbová, William C Stewart, Carlotta Stipa, Pasquale Striano, Adam Strzelczyk, Rainer Surges, Toshimitsu Suzuki, Mariagrazia Talarico, Michael E Talkowski, Randip S Taneja, George A Tanteles, Oskari Timonen, Nicholas John Timpson, Paolo Tinuper, Marian Todaro, Pınar Topaloglu, Meng-Han Tsai, Birute Tumiene, Dilsad Turkdogan, Sibel Uğur-İşeri, Algirdas Utkus, Priya Vaidiswaran, Luc Valton, Andreas van Baalen, Maria Stella Vari, Annalisa Vetro, Markéta Vlčková, Sophie von Brauchitsch, Sarah von Spiczak, Ryan G Wagner, Nick Watts, Yvonne G Weber, Sarah Weckhuysen, Peter Widdess-Walsh, Samuel Wiebe, Steven M Wolf, Markus Wolff, Stefan Wolking, Isaac Wong, Randi von Wrede, David Wu, Kazuhiro Yamakawa, Zuhal Yapıcı, Uluc Yis, Robert Yolken, Emrah Yücesan, Sara Zagaglia, Felix Zahnert, Federico Zara, Fritz Zimprich, Milena Zizovic, Gábor Zsurka, Benjamin M Neale, Samuel F Berkovic
{"title":"Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.","authors":"Siwei Chen, Bassel W Abou-Khalil, Zaid Afawi, Quratulain Zulfiqar Ali, Elisabetta Amadori, Alison Anderson, Joe Anderson, Danielle M Andrade, Grazia Annesi, Mutluay Arslan, Pauls Auce, Melanie Bahlo, Mark D Baker, Ganna Balagura, Simona Balestrini, Eric Banks, Carmen Barba, Karen Barboza, Fabrice Bartolomei, Nick Bass, Larry W Baum, Tobias H Baumgartner, Betül Baykan, Nerses Bebek, Felicitas Becker, Caitlin A Bennett, Ahmad Beydoun, Claudia Bianchini, Francesca Bisulli, Douglas Blackwood, Ilan Blatt, Ingo Borggräfe, Christian Bosselmann, Vera Braatz, Harrison Brand, Knut Brockmann, Russell J Buono, Robyn M Busch, S Hande Caglayan, Laura Canafoglia, Christina Canavati, Barbara Castellotti, Gianpiero L Cavalleri, Felecia Cerrato, Francine Chassoux, Christina Cherian, Stacey S Cherny, Ching-Lung Cheung, I-Jun Chou, Seo-Kyung Chung, Claire Churchhouse, Valentina Ciullo, Peggy O Clark, Andrew J Cole, Mahgenn Cosico, Patrick Cossette, Chris Cotsapas, Caroline Cusick, Mark J Daly, Lea K Davis, Peter De Jonghe, Norman Delanty, Dieter Dennig, Chantal Depondt, Philippe Derambure, Orrin Devinsky, Lidia Di Vito, Faith Dickerson, Dennis J Dlugos, Viola Doccini, Colin P Doherty, Hany El-Naggar, Colin A Ellis, Leon Epstein, Meghan Evans, Annika Faucon, Yen-Chen Anne Feng, Lisa Ferguson, Thomas N Ferraro, Izabela Ferreira Da Silva, Lorenzo Ferri, Martha Feucht, Madeline C Fields, Mark Fitzgerald, Beata Fonferko-Shadrach, Francesco Fortunato, Silvana Franceschetti, Jacqueline A French, Elena Freri, Jack M Fu, Stacey Gabriel, Monica Gagliardi, Antonio Gambardella, Laura Gauthier, Tania Giangregorio, Tommaso Gili, Tracy A Glauser, Ethan Goldberg, Alica Goldman, David B Goldstein, Tiziana Granata, Riley Grant, David A Greenberg, Renzo Guerrini, Aslı Gundogdu-Eken, Namrata Gupta, Kevin Haas, Hakon Hakonarson, Garen Haryanyan, Martin Häusler, Manu Hegde, Erin L Heinzen, Ingo Helbig, Christian Hengsbach, Henrike Heyne, Shinichi Hirose, Edouard Hirsch, Chen-Jui Ho, Olivia Hoeper, Daniel P Howrigan, Donald Hucks, Po-Chen Hung, Michele Iacomino, Yushi Inoue, Luciana Midori Inuzuka, Atsushi Ishii, Lara Jehi, Michael R Johnson, Mandy Johnstone, Reetta Kälviäinen, Moien Kanaan, Bulent Kara, Symon M Kariuki, Josua Kegele, Yeşim Kesim, Nathalie Khoueiry-Zgheib, Jean Khoury, Chontelle King, Karl Martin Klein, Gerhard Kluger, Susanne Knake, Fernando Kok, Amos D Korczyn, Rudolf Korinthenberg, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Martin Krenn, Heinz Krestel, Ilona Krey, Wolfram S Kunz, Gerhard Kurlemann, Ruben I Kuzniecky, Patrick Kwan, Maite La Vega-Talbott, Angelo Labate, Austin Lacey, Dennis Lal, Petra Laššuthová, Stephan Lauxmann, Charlotte Lawthom, Stephanie L Leech, Anna-Elina Lehesjoki, Johannes R Lemke, Holger Lerche, Gaetan Lesca, Costin Leu, Naomi Lewin, David Lewis-Smith, Gloria Hoi-Yee Li, Calwing Liao, Laura Licchetta, Chih-Hsiang Lin, Kuang-Lin Lin, Tarja Linnankivi, Warren Lo, Daniel H Lowenstein, Chelsea Lowther, Laura Lubbers, Colin H T Lui, Lucia Inês Macedo-Souza, Rene Madeleyn, Francesca Madia, Stefania Magri, Louis Maillard, Lara Marcuse, Paula Marques, Anthony G Marson, Abigail G Matthews, Patrick May, Thomas Mayer, Wendy McArdle, Steven M McCarroll, Patricia McGoldrick, Christopher M McGraw, Andrew McIntosh, Andrew McQuillan, Kimford J Meador, Davide Mei, Véronique Michel, John J Millichap, Raffaella Minardi, Martino Montomoli, Barbara Mostacci, Lorenzo Muccioli, Hiltrud Muhle, Karen Müller-Schlüter, Imad M Najm, Wassim Nasreddine, Samuel Neaves, Bernd A Neubauer, Charles R J C Newton, Jeffrey L Noebels, Kate Northstone, Sam Novod, Terence J O'Brien, Seth Owusu-Agyei, Çiğdem Özkara, Aarno Palotie, Savvas S Papacostas, Elena Parrini, Carlos Pato, Michele Pato, Manuela Pendziwiat, Page B Pennell, Slavé Petrovski, William O Pickrell, Rebecca Pinsky, Dalila Pinto, Tommaso Pippucci, Fabrizio Piras, Federica Piras, Annapurna Poduri, Federica Pondrelli, Danielle Posthuma, Robert H W Powell, Michael Privitera, Annika Rademacher, Francesca Ragona, Byron Ramirez-Hamouz, Sarah Rau, Hillary R Raynes, Mark I Rees, Brigid M Regan, Andreas Reif, Eva Reinthaler, Sylvain Rheims, Susan M Ring, Antonella Riva, Enrique Rojas, Felix Rosenow, Philippe Ryvlin, Anni Saarela, Lynette G Sadleir, Barış Salman, Andrea Salmon, Vincenzo Salpietro, Ilaria Sammarra, Marcello Scala, Steven Schachter, André Schaller, Christoph J Schankin, Ingrid E Scheffer, Natascha Schneider, Susanne Schubert-Bast, Andreas Schulze-Bonhage, Paolo Scudieri, Lucie Sedláčková, Catherine Shain, Pak C Sham, Beth R Shiedley, S Anthony Siena, Graeme J Sills, Sanjay M Sisodiya, Jordan W Smoller, Matthew Solomonson, Gianfranco Spalletta, Kathryn R Sparks, Michael R Sperling, Hannah Stamberger, Bernhard J Steinhoff, Ulrich Stephani, Katalin Štěrbová, William C Stewart, Carlotta Stipa, Pasquale Striano, Adam Strzelczyk, Rainer Surges, Toshimitsu Suzuki, Mariagrazia Talarico, Michael E Talkowski, Randip S Taneja, George A Tanteles, Oskari Timonen, Nicholas John Timpson, Paolo Tinuper, Marian Todaro, Pınar Topaloglu, Meng-Han Tsai, Birute Tumiene, Dilsad Turkdogan, Sibel Uğur-İşeri, Algirdas Utkus, Priya Vaidiswaran, Luc Valton, Andreas van Baalen, Maria Stella Vari, Annalisa Vetro, Markéta Vlčková, Sophie von Brauchitsch, Sarah von Spiczak, Ryan G Wagner, Nick Watts, Yvonne G Weber, Sarah Weckhuysen, Peter Widdess-Walsh, Samuel Wiebe, Steven M Wolf, Markus Wolff, Stefan Wolking, Isaac Wong, Randi von Wrede, David Wu, Kazuhiro Yamakawa, Zuhal Yapıcı, Uluc Yis, Robert Yolken, Emrah Yücesan, Sara Zagaglia, Felix Zahnert, Federico Zara, Fritz Zimprich, Milena Zizovic, Gábor Zsurka, Benjamin M Neale, Samuel F Berkovic","doi":"10.1101/2023.02.22.23286310","DOIUrl":null,"url":null,"abstract":"<p><p>Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980234/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv : the preprint server for health sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.02.22.23286310","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.
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