Медицинская библиотека · medRxiv : the preprint server for health sciences · 2024
Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.
Chen Siwei, Abou-Khalil Bassel W, Afawi Zaid, Ali Quratulain Zulfiqar, Amadori Elisabetta, Anderson Alison, Anderson Joe, Andrade Danielle M, Annesi Grazia, Arslan Mutluay, Auce Pauls, Bahlo Melanie, Baker Mark D, Balagura Ganna, Balestrini Simona, Banks Eric, Barba Carmen, Barboza Karen, Bartolomei Fabrice, Bass Nick, Baum Larry W, Baumgartner Tobias H, Baykan Betül, Bebek Nerses, Becker Felicitas, Bennett Caitlin A, Beydoun Ahmad, Bianchini Claudia, Bisulli Francesca, Blackwood Douglas, Blatt Ilan, Borggräfe Ingo, Bosselmann Christian, Braatz Vera, Brand Harrison, Brockmann Knut, Buono Russell J, Busch Robyn M, Caglayan S Hande, Canafoglia Laura, Canavati Christina, Castellotti Barbara, Cavalleri Gianpiero L, Cerrato Felecia, Chassoux Francine, Cherian Christina, Cherny Stacey S, Cheung Ching-Lung, Chou I-Jun, Chung Seo-Kyung, Churchhouse Claire, Ciullo Valentina, Clark Peggy O, Cole Andrew J, Cosico Mahgenn, Cossette Patrick, Cotsapas Chris, Cusick Caroline, Daly Mark J, Davis Lea K, Jonghe Peter De, Delanty Norman, Dennig Dieter, Depondt Chantal, Derambure Philippe, Devinsky Orrin, Di Vito Lidia, Dickerson Faith, Dlugos Dennis J, Doccini Viola, Doherty Colin P, El-Naggar Hany, Ellis Colin A, Epstein Leon, Evans Meghan, Faucon Annika, Feng Yen-Chen Anne, Ferguson Lisa, Ferraro Thomas N, Da Silva Izabela Ferreira, Ferri Lorenzo, Feucht Martha, Fields Madeline C, Fitzgerald Mark, Fonferko-Shadrach Beata, Fortunato Francesco, Franceschetti Silvana, French Jacqueline A, Freri Elena, Fu Jack M, Gabriel Stacey, Gagliardi Monica, Gambardella Antonio, Gauthier Laura, Giangregorio Tania, Gili Tommaso, Glauser Tracy A, Goldberg Ethan, Goldman Alica, Goldstein David B, Granata Tiziana, Grant Riley, Greenberg David A, Guerrini Renzo, Gundogdu-Eken Aslı, Gupta Namrata, Haas Kevin, Hakonarson Hakon, Haryanyan Garen, Häusler Martin, Hegde Manu, Heinzen Erin L, Helbig Ingo, Hengsbach Christian, Heyne Henrike, Hirose Shinichi, Hirsch Edouard, Ho Chen-Jui, Hoeper Olivia, Howrigan Daniel P, Hucks Donald, Hung Po-Chen, Iacomino Michele, Inoue Yushi, Inuzuka Luciana Midori, Ishii Atsushi, Jehi Lara, Johnson Michael R, Johnstone Mandy, Kälviäinen Reetta, Kanaan Moien, Kara Bulent, Kariuki Symon M, Kegele Josua, Kesim Yeşim, Khoueiry-Zgheib Nathalie, Khoury Jean, King Chontelle, Klein Karl Martin, Kluger Gerhard, Knake Susanne, Kok Fernando, Korczyn Amos D, Korinthenberg Rudolf, Koupparis Andreas, Kousiappa Ioanna, Krause Roland, Krenn Martin, Krestel Heinz, Krey Ilona, Kunz Wolfram S, Kurlemann Gerhard, Kuzniecky Ruben I, Kwan Patrick, La Vega-Talbott Maite, Labate Angelo, Lacey Austin, Lal Dennis, Laššuthová Petra, Lauxmann Stephan, Lawthom Charlotte, Leech Stephanie L, Lehesjoki Anna-Elina, Lemke Johannes R, Lerche Holger, Lesca Gaetan, Leu Costin, Lewin Naomi, Lewis-Smith David, Li Gloria Hoi-Yee, Liao Calwing, Licchetta Laura, Lin Chih-Hsiang, Lin Kuang-Lin, Linnankivi Tarja, Lo Warren, Lowenstein Daniel H, Lowther Chelsea, Lubbers Laura, Lui Colin H T, Macedo-Souza Lucia Inês, Madeleyn Rene, Madia Francesca, Magri Stefania, Maillard Louis, Marcuse Lara, Marques Paula, Marson Anthony G, Matthews Abigail G, May Patrick, Mayer Thomas, McArdle Wendy, McCarroll Steven M, McGoldrick Patricia, McGraw Christopher M, McIntosh Andrew, McQuillan Andrew, Meador Kimford J, Mei Davide, Michel Véronique, Millichap John J, Minardi Raffaella, Montomoli Martino, Mostacci Barbara, Muccioli Lorenzo, Muhle Hiltrud, Müller-Schlüter Karen, Najm Imad M, Nasreddine Wassim, Neaves Samuel, Neubauer Bernd A, Newton Charles R J C, Noebels Jeffrey L, Northstone Kate, Novod Sam, O'Brien Terence J, Owusu-Agyei Seth, Özkara Çiğdem, Palotie Aarno, Papacostas Savvas S, Parrini Elena, Pato Carlos, Pato Michele, Pendziwiat Manuela, Pennell Page B, Petrovski Slavé, Pickrell William O, Pinsky Rebecca, Pinto Dalila, Pippucci Tommaso, Piras Fabrizio, Piras Federica, Poduri Annapurna, Pondrelli Federica, Posthuma Danielle, Powell Robert H W, Privitera Michael, Rademacher Annika, Ragona Francesca, Ramirez-Hamouz Byron, Rau Sarah, Raynes Hillary R, Rees Mark I, Regan Brigid M, Reif Andreas, Reinthaler Eva, Rheims Sylvain, Ring Susan M, Riva Antonella, Rojas Enrique, Rosenow Felix, Ryvlin Philippe, Saarela Anni, Sadleir Lynette G, Salman Barış, Salmon Andrea, Salpietro Vincenzo, Sammarra Ilaria, Scala Marcello, Schachter Steven, Schaller André, Schankin Christoph J, Scheffer Ingrid E, Schneider Natascha, Schubert-Bast Susanne, Schulze-Bonhage Andreas, Scudieri Paolo, Sedláčková Lucie, Shain Catherine, Sham Pak C, Shiedley Beth R, Siena S Anthony, Sills Graeme J, Sisodiya Sanjay M, Smoller Jordan W, Solomonson Matthew, Spalletta Gianfranco, Sparks Kathryn R, Sperling Michael R, Stamberger Hannah, Steinhoff Bernhard J, Stephani Ulrich, Štěrbová Katalin, Stewart William C, Stipa Carlotta, Striano Pasquale, Strzelczyk Adam, Surges Rainer, Suzuki Toshimitsu, Talarico Mariagrazia, Talkowski Michael E, Taneja Randip S, Tanteles George A, Timonen Oskari, Timpson Nicholas John, Tinuper Paolo, Todaro Marian, Topaloglu Pınar, Tsai Meng-Han, Tumiene Birute, Turkdogan Dilsad, Uğur-İşeri Sibel, Utkus Algirdas, Vaidiswaran Priya, Valton Luc, van Baalen Andreas, Vari Maria Stella, Vetro Annalisa, Vlčková Markéta, von Brauchitsch Sophie, von Spiczak Sarah, Wagner Ryan G, Watts Nick, Weber Yvonne G, Weckhuysen Sarah, Widdess-Walsh Peter, Wiebe Samuel, Wolf Steven M, Wolff Markus, Wolking Stefan, Wong Isaac, von Wrede Randi, Wu David, Yamakawa Kazuhiro, Yapıcı Zuhal, Yis Uluc, Yolken Robert, Yücesan Emrah, Zagaglia Sara, Zahnert Felix, Zara Federico, Zimprich Fritz, Zizovic Milena, Zsurka Gábor, Neale Benjamin M, Berkovic Samuel F
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Аннотация
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.
Для цитирования: Chen Siwei, Abou-Khalil Bassel W, Afawi Zaid, Ali Quratulain Zulfiqar, Amadori Elisabetta, Anderson Alison, Anderson Joe, Andrade Danielle M, Annesi Grazia, Arslan Mutluay, Auce Pauls, Bahlo Melanie, Baker Mark D, Balagura Ganna, Balestrini Simona, Banks Eric, Barba Carmen, Barboza Karen, Bartolomei Fabrice, Bass Nick, Baum Larry W, Baumgartner Tobias H, Baykan Betül, Bebek Nerses, Becker Felicitas, Bennett Caitlin A, Beydoun Ahmad, Bianchini Claudia, Bisulli Francesca, Blackwood Douglas, Blatt Ilan, Borggräfe Ingo, Bosselmann Christian, Braatz Vera, Brand Harrison, Brockmann Knut, Buono Russell J, Busch Robyn M, Caglayan S Hande, Canafoglia Laura, Canavati Christina, Castellotti Barbara, Cavalleri Gianpiero L, Cerrato Felecia, Chassoux Francine, Cherian Christina, Cherny Stacey S, Cheung Ching-Lung, Chou I-Jun, Chung Seo-Kyung, Churchhouse Claire, Ciullo Valentina, Clark Peggy O, Cole Andrew J, Cosico Mahgenn, Cossette Patrick, Cotsapas Chris, Cusick Caroline, Daly Mark J, Davis Lea K, Jonghe Peter De, Delanty Norman, Dennig Dieter, Depondt Chantal, Derambure Philippe, Devinsky Orrin, Di Vito Lidia, Dickerson Faith, Dlugos Dennis J, Doccini Viola, Doherty Colin P, El-Naggar Hany, Ellis Colin A, Epstein Leon, Evans Meghan, Faucon Annika, Feng Yen-Chen Anne, Ferguson Lisa, Ferraro Thomas N, Da Silva Izabela Ferreira, Ferri Lorenzo, Feucht Martha, Fields Madeline C, Fitzgerald Mark, Fonferko-Shadrach Beata, Fortunato Francesco, Franceschetti Silvana, French Jacqueline A, Freri Elena, Fu Jack M, Gabriel Stacey, Gagliardi Monica, Gambardella Antonio, Gauthier Laura, Giangregorio Tania, Gili Tommaso, Glauser Tracy A, Goldberg Ethan, Goldman Alica, Goldstein David B, Granata Tiziana, Grant Riley, Greenberg David A, Guerrini Renzo, Gundogdu-Eken Aslı, Gupta Namrata, Haas Kevin, Hakonarson Hakon, Haryanyan Garen, Häusler Martin, Hegde Manu, Heinzen Erin L, Helbig Ingo, Hengsbach Christian, Heyne Henrike, Hirose Shinichi, Hirsch Edouard, Ho Chen-Jui, Hoeper Olivia, Howrigan Daniel P, Hucks Donald, Hung Po-Chen, Iacomino Michele, Inoue Yushi, Inuzuka Luciana Midori, Ishii Atsushi, Jehi Lara, Johnson Michael R, Johnstone Mandy, Kälviäinen Reetta, Kanaan Moien, Kara Bulent, Kariuki Symon M, Kegele Josua, Kesim Yeşim, Khoueiry-Zgheib Nathalie, Khoury Jean, King Chontelle, Klein Karl Martin, Kluger Gerhard, Knake Susanne, Kok Fernando, Korczyn Amos D, Korinthenberg Rudolf, Koupparis Andreas, Kousiappa Ioanna, Krause Roland, Krenn Martin, Krestel Heinz, Krey Ilona, Kunz Wolfram S, Kurlemann Gerhard, Kuzniecky Ruben I, Kwan Patrick, La Vega-Talbott Maite, Labate Angelo, Lacey Austin, Lal Dennis, Laššuthová Petra, Lauxmann Stephan, Lawthom Charlotte, Leech Stephanie L, Lehesjoki Anna-Elina, Lemke Johannes R, Lerche Holger, Lesca Gaetan, Leu Costin, Lewin Naomi, Lewis-Smith David, Li Gloria Hoi-Yee, Liao Calwing, Licchetta Laura, Lin Chih-Hsiang, Lin Kuang-Lin, Linnankivi Tarja, Lo Warren, Lowenstein Daniel H, Lowther Chelsea, Lubbers Laura, Lui Colin H T, Macedo-Souza Lucia Inês, Madeleyn Rene, Madia Francesca, Magri Stefania, Maillard Louis, Marcuse Lara, Marques Paula, Marson Anthony G, Matthews Abigail G, May Patrick, Mayer Thomas, McArdle Wendy, McCarroll Steven M, McGoldrick Patricia, McGraw Christopher M, McIntosh Andrew, McQuillan Andrew, Meador Kimford J, Mei Davide, Michel Véronique, Millichap John J, Minardi Raffaella, Montomoli Martino, Mostacci Barbara, Muccioli Lorenzo, Muhle Hiltrud, Müller-Schlüter Karen, Najm Imad M, Nasreddine Wassim, Neaves Samuel, Neubauer Bernd A, Newton Charles R J C, Noebels Jeffrey L, Northstone Kate, Novod Sam, O'Brien Terence J, Owusu-Agyei Seth, Özkara Çiğdem, Palotie Aarno, Papacostas Savvas S, Parrini Elena, Pato Carlos, Pato Michele, Pendziwiat Manuela, Pennell Page B, Petrovski Slavé, Pickrell William O, Pinsky Rebecca, Pinto Dalila, Pippucci Tommaso, Piras Fabrizio, Piras Federica, Poduri Annapurna, Pondrelli Federica, Posthuma Danielle, Powell Robert H W, Privitera Michael, Rademacher Annika, Ragona Francesca, Ramirez-Hamouz Byron, Rau Sarah, Raynes Hillary R, Rees Mark I, Regan Brigid M, Reif Andreas, Reinthaler Eva, Rheims Sylvain, Ring Susan M, Riva Antonella, Rojas Enrique, Rosenow Felix, Ryvlin Philippe, Saarela Anni, Sadleir Lynette G, Salman Barış, Salmon Andrea, Salpietro Vincenzo, Sammarra Ilaria, Scala Marcello, Schachter Steven, Schaller André, Schankin Christoph J, Scheffer Ingrid E, Schneider Natascha, Schubert-Bast Susanne, Schulze-Bonhage Andreas, Scudieri Paolo, Sedláčková Lucie, Shain Catherine, Sham Pak C, Shiedley Beth R, Siena S Anthony, Sills Graeme J, Sisodiya Sanjay M, Smoller Jordan W, Solomonson Matthew, Spalletta Gianfranco, Sparks Kathryn R, Sperling Michael R, Stamberger Hannah, Steinhoff Bernhard J, Stephani Ulrich, Štěrbová Katalin, Stewart William C, Stipa Carlotta, Striano Pasquale, Strzelczyk Adam, Surges Rainer, Suzuki Toshimitsu, Talarico Mariagrazia, Talkowski Michael E, Taneja Randip S, Tanteles George A, Timonen Oskari, Timpson Nicholas John, Tinuper Paolo, Todaro Marian, Topaloglu Pınar, Tsai Meng-Han, Tumiene Birute, Turkdogan Dilsad, Uğur-İşeri Sibel, Utkus Algirdas, Vaidiswaran Priya, Valton Luc, van Baalen Andreas, Vari Maria Stella, Vetro Annalisa, Vlčková Markéta, von Brauchitsch Sophie, von Spiczak Sarah, Wagner Ryan G, Watts Nick, Weber Yvonne G, Weckhuysen Sarah, Widdess-Walsh Peter, Wiebe Samuel, Wolf Steven M, Wolff Markus, Wolking Stefan, Wong Isaac, von Wrede Randi, Wu David, Yamakawa Kazuhiro, Yapıcı Zuhal, Yis Uluc, Yolken Robert, Yücesan Emrah, Zagaglia Sara, Zahnert Felix, Zara Federico, Zimprich Fritz, Zizovic Milena, Zsurka Gábor, Neale Benjamin M, Berkovic Samuel F. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.. medRxiv : the preprint server for health sciences. 2024. DOI: 10.1101/2023.02.22.23286310.
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