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Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Allen, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, André Schaller, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Yiolanda Christou, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Gábor Zsurka, Rainer Surges, Tobias Baumgartner, Randi von Wrede, 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 Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengsbach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Ingo Borggräfe, Christoph J. Schankin, Susanne Schubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Véronique Michel, Francine Chassoux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Lawthom, Joseph Anderson, 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, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barišić, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, Antonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpietro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisabetta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lorenzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, Atsushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Pınar Topaloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, YeşÇiğdem Özkara, Meng-Han Tsai, Chen-Jui Ho, Chih-Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, 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, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidiswaran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein

The American Journal of Human Genetics, Volume: 108, Issue: 6, Pages: 965 - 982

Swansea University Author: Robert Powell

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DOI (Published version): 10.1016/j.ajhg.2021.04.009

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control in...

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Published in: The American Journal of Human Genetics
ISSN: 0002-9297
Published: Elsevier BV 2021
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa60620
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2022-08-15T12:55:27.3235419</datestamp><bib-version>v2</bib-version><id>60620</id><entry>2022-07-25</entry><title>Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals</title><swanseaauthors><author><sid>7c8ac48bb6ae4281930e4138f94a51b6</sid><firstname>Robert</firstname><surname>Powell</surname><name>Robert Powell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-07-25</date><abstract>Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.</abstract><type>Journal Article</type><journal>The American Journal of Human Genetics</journal><volume>108</volume><journalNumber>6</journalNumber><paginationStart>965</paginationStart><paginationEnd>982</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0002-9297</issnPrint><issnElectronic/><keywords>epilepsy; epileptic encephalopathy; seizures; whole-exome sequencing; focal epilepsy; generalized epilepsy; intolerance; ClinVar; Epi25; Louvain</keywords><publishedDay>3</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-06-03</publishedDate><doi>10.1016/j.ajhg.2021.04.009</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm/><funders>J.E.M. is supported by the National Institutes of Health (TL1TR001875). This work is part of 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). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, and Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088.</funders><projectreference/><lastEdited>2022-08-15T12:55:27.3235419</lastEdited><Created>2022-07-25T11:09:23.4525565</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Joshua E.</firstname><surname>Motelow</surname><order>1</order></author><author><firstname>Gundula</firstname><surname>Povysil</surname><order>2</order></author><author><firstname>Ryan S.</firstname><surname>Dhindsa</surname><order>3</order></author><author><firstname>Kate E.</firstname><surname>Stanley</surname><order>4</order></author><author><firstname>Andrew S.</firstname><surname>Allen</surname><order>5</order></author><author><firstname>Yen-Chen Anne</firstname><surname>Feng</surname><order>6</order></author><author><firstname>Daniel P.</firstname><surname>Howrigan</surname><order>7</order></author><author><firstname>Liam E.</firstname><surname>Abbott</surname><order>8</order></author><author><firstname>Katherine</firstname><surname>Tashman</surname><order>9</order></author><author><firstname>Felecia</firstname><surname>Cerrato</surname><order>10</order></author><author><firstname>Caroline</firstname><surname>Cusick</surname><order>11</order></author><author><firstname>Tarjinder</firstname><surname>Singh</surname><order>12</order></author><author><firstname>Henrike</firstname><surname>Heyne</surname><order>13</order></author><author><firstname>Andrea E.</firstname><surname>Byrnes</surname><order>14</order></author><author><firstname>Claire</firstname><surname>Churchhouse</surname><order>15</order></author><author><firstname>Nick</firstname><surname>Watts</surname><order>16</order></author><author><firstname>Matthew</firstname><surname>Solomonson</surname><order>17</order></author><author><firstname>Dennis</firstname><surname>Lal</surname><order>18</order></author><author><firstname>Namrata</firstname><surname>Gupta</surname><order>19</order></author><author><firstname>Benjamin M.</firstname><surname>Neale</surname><order>20</order></author><author><firstname>Gianpiero L.</firstname><surname>Cavalleri</surname><order>21</order></author><author><firstname>Patrick</firstname><surname>Cossette</surname><order>22</order></author><author><firstname>Chris</firstname><surname>Cotsapas</surname><order>23</order></author><author><firstname>Peter 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spelling 2022-08-15T12:55:27.3235419 v2 60620 2022-07-25 Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals 7c8ac48bb6ae4281930e4138f94a51b6 Robert Powell Robert Powell true false 2022-07-25 Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy. Journal Article The American Journal of Human Genetics 108 6 965 982 Elsevier BV 0002-9297 epilepsy; epileptic encephalopathy; seizures; whole-exome sequencing; focal epilepsy; generalized epilepsy; intolerance; ClinVar; Epi25; Louvain 3 6 2021 2021-06-03 10.1016/j.ajhg.2021.04.009 COLLEGE NANME COLLEGE CODE Swansea University J.E.M. is supported by the National Institutes of Health (TL1TR001875). This work is part of 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). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, and Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088. 2022-08-15T12:55:27.3235419 2022-07-25T11:09:23.4525565 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Joshua E. Motelow 1 Gundula Povysil 2 Ryan S. Dhindsa 3 Kate E. Stanley 4 Andrew S. Allen 5 Yen-Chen Anne Feng 6 Daniel P. Howrigan 7 Liam E. Abbott 8 Katherine Tashman 9 Felecia Cerrato 10 Caroline Cusick 11 Tarjinder Singh 12 Henrike Heyne 13 Andrea E. Byrnes 14 Claire Churchhouse 15 Nick Watts 16 Matthew Solomonson 17 Dennis Lal 18 Namrata Gupta 19 Benjamin M. Neale 20 Gianpiero L. Cavalleri 21 Patrick Cossette 22 Chris Cotsapas 23 Peter De Jonghe 24 Tracy Dixon-Salazar 25 Renzo Guerrini 26 Hakon Hakonarson 27 Erin L. Heinzen 28 Ingo Helbig 29 Patrick Kwan 30 Anthony G. Marson 31 Slavé Petrovski 32 Sitharthan Kamalakaran 33 Sanjay M. Sisodiya 34 Randy Stewart 35 Sarah Weckhuysen 36 Chantal Depondt 37 Dennis J. Dlugos 38 Ingrid E. Scheffer 39 Pasquale Striano 40 Catharine Freyer 41 Roland Krause 42 Patrick May 43 Kevin McKenna 44 Brigid M. Regan 45 Caitlin A. Bennett 46 Costin Leu 47 Stephanie L. Leech 48 Terence J. O’Brien 49 Marian Todaro 50 Hannah Stamberger 51 Danielle M. Andrade 52 Quratulain Zulfiqar Ali 53 Tara R. Sadoway 54 Heinz Krestel 55 André Schaller 56 Savvas S. Papacostas 57 Ioanna Kousiappa 58 George A. Tanteles 59 Yiolanda Christou 60 Katalin Štěrbová 61 Markéta Vlčková 62 Lucie Sedláčková 63 Petra Laššuthová 64 Karl Martin Klein 65 Felix Rosenow 66 Philipp S. Reif 67 Susanne Knake 68 Bernd A. Neubauer 69 Friedrich Zimprich 70 Martha Feucht 71 Eva M. Reinthaler 72 Wolfram S. Kunz 73 Gábor Zsurka 74 Rainer Surges 75 Tobias Baumgartner 76 Randi von Wrede 77 Manuela Pendziwiat 78 Hiltrud Muhle 79 Annika Rademacher 80 Andreas van Baalen 81 Sarah von Spiczak 82 Ulrich Stephani 83 Zaid Afawi 84 Amos D. Korczyn 85 Moien Kanaan 86 Christina Canavati 87 Gerhard Kurlemann 88 Karen Müller-Schlüter 89 Gerhard Kluger 90 Martin Häusler 91 Ilan Blatt 92 Johannes R. Lemke 93 Ilona Krey 94 Yvonne G. Weber 95 Stefan Wolking 96 Felicitas Becker 97 Stephan Lauxmann 98 Christian Boßelmann 99 Josua Kegele 100 Christian Hengsbach 101 Sarah Rau 102 Bernhard J. Steinhoff 103 Andreas Schulze-Bonhage 104 Ingo Borggräfe 105 Christoph J. Schankin 106 Susanne Schubert-Bast 107 Herbert Schreiber 108 Thomas Mayer 109 Rudolf Korinthenberg 110 Knut Brockmann 111 Markus Wolff 112 Dieter Dennig 113 Rene Madeleyn 114 Reetta Kälviäinen 115 Anni Saarela 116 Oskari Timonen 117 Tarja Linnankivi 118 Anna-Elina Lehesjoki 119 Sylvain Rheims 120 Gaetan Lesca 121 Philippe Ryvlin 122 Louis Maillard 123 Luc Valton 124 Philippe Derambure 125 Fabrice Bartolomei 126 Edouard Hirsch 127 Véronique Michel 128 Francine Chassoux 129 Mark I. Rees 130 Seo-Kyung Chung 131 William O. Pickrell 132 Robert Powell 133 Mark D. Baker 134 Beata Fonferko-Shadrach 135 Charlotte Lawthom 136 Joseph Anderson 137 Natascha Schneider 138 Simona Balestrini 139 Sara Zagaglia 140 Vera Braatz 141 Michael R. Johnson 142 Pauls Auce 143 Graeme J. Sills 144 Larry W. Baum 145 Pak C. Sham 146 Stacey S. Cherny 147 Colin H.T. Lui 148 Norman Delanty 149 Colin P. Doherty 150 Arif Shukralla 151 Hany El-Naggar 152 Peter Widdess-Walsh 153 Nina Barišić 154 Laura Canafoglia 155 Silvana Franceschetti 156 Barbara Castellotti 157 Tiziana Granata 158 Francesca Ragona 159 Federico Zara 160 Michele Iacomino 161 Antonella Riva 162 Francesca Madia 163 Maria Stella Vari 164 Vincenzo Salpietro 165 Marcello Scala 166 Maria Margherita Mancardi 167 Lino Nobili 168 Elisabetta Amadori 169 Thea Giacomini 170 Francesca Bisulli 171 Tommaso Pippucci 172 Laura Licchetta 173 Raffaella Minardi 174 Paolo Tinuper 175 Lorenzo Muccioli 176 Barbara Mostacci 177 Antonio Gambardella 178 Angelo Labate 179 Grazia Annesi 180 Lorella Manna 181 Monica Gagliardi 182 Elena Parrini 183 Davide Mei 184 Annalisa Vetro 185 Claudia Bianchini 186 Martino Montomoli 187 Viola Doccini 188 Carmen Barba 189 Shinichi Hirose 190 Atsushi Ishii 191 Toshimitsu Suzuki 192 Yushi Inoue 193 Kazuhiro Yamakawa 194 Ahmad Beydoun 195 Wassim Nasreddine 196 Nathalie Khoueiry Zgheib 197 Birute Tumiene 198 Algirdas Utkus 199 Lynette G. Sadleir 200 Chontelle King 201 S. Hande Caglayan 202 Mutluay Arslan 203 Zuhal Yapıcı 204 Pınar Topaloglu 205 Bulent Kara 206 Uluc Yis 207 Dilsad Turkdogan 208 Aslı Gundogdu-Eken 209 Nerses Bebek 210 Sibel Uğur-İşeri 211 Betül Baykan 212 Barış Salman 213 Garen Haryanyan 214 Emrah Yücesan 215 Yeşim Kesim 216 YeşÇiğdem Özkara 217 Meng-Han Tsai 218 Chen-Jui Ho 219 Chih-Hsiang Lin 220 Kuang-Lin Lin 221 I-Jun Chou 222 Annapurna Poduri 223 Beth R. Shiedley 224 Catherine Shain 225 Jeffrey L. Noebels 226 Alicia Goldman 227 Robyn M. Busch 228 Lara Jehi 229 Imad M. Najm 230 Lisa Ferguson 231 Jean Khoury 232 Tracy A. Glauser 233 Peggy O. Clark 234 Russell J. Buono 235 Thomas N. Ferraro 236 Michael R. Sperling 237 Warren Lo 238 Michael Privitera 239 Jacqueline A. French 240 Steven Schachter 241 Ruben I. Kuzniecky 242 Orrin Devinsky 243 Manu Hegde 244 David A. Greenberg 245 Colin A. Ellis 246 Ethan Goldberg 247 Katherine L. Helbig 248 Mahgenn Cosico 249 Priya Vaidiswaran 250 Eryn Fitch 251 Samuel F. Berkovic 252 Holger Lerche 253 Daniel H. Lowenstein 254 David B. Goldstein 255
title Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
spellingShingle Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
Robert Powell
title_short Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
title_full Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
title_fullStr Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
title_full_unstemmed Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
title_sort Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
author_id_str_mv 7c8ac48bb6ae4281930e4138f94a51b6
author_id_fullname_str_mv 7c8ac48bb6ae4281930e4138f94a51b6_***_Robert Powell
author Robert Powell
author2 Joshua E. Motelow
Gundula Povysil
Ryan S. Dhindsa
Kate E. Stanley
Andrew S. Allen
Yen-Chen Anne Feng
Daniel P. Howrigan
Liam E. Abbott
Katherine Tashman
Felecia Cerrato
Caroline Cusick
Tarjinder Singh
Henrike Heyne
Andrea E. Byrnes
Claire Churchhouse
Nick Watts
Matthew Solomonson
Dennis Lal
Namrata Gupta
Benjamin M. Neale
Gianpiero L. Cavalleri
Patrick Cossette
Chris Cotsapas
Peter De Jonghe
Tracy Dixon-Salazar
Renzo Guerrini
Hakon Hakonarson
Erin L. Heinzen
Ingo Helbig
Patrick Kwan
Anthony G. Marson
Slavé Petrovski
Sitharthan Kamalakaran
Sanjay M. Sisodiya
Randy Stewart
Sarah Weckhuysen
Chantal Depondt
Dennis J. Dlugos
Ingrid E. Scheffer
Pasquale Striano
Catharine Freyer
Roland Krause
Patrick May
Kevin McKenna
Brigid M. Regan
Caitlin A. Bennett
Costin Leu
Stephanie L. Leech
Terence J. O’Brien
Marian Todaro
Hannah Stamberger
Danielle M. Andrade
Quratulain Zulfiqar Ali
Tara R. Sadoway
Heinz Krestel
André Schaller
Savvas S. Papacostas
Ioanna Kousiappa
George A. Tanteles
Yiolanda Christou
Katalin Štěrbová
Markéta Vlčková
Lucie Sedláčková
Petra Laššuthová
Karl Martin Klein
Felix Rosenow
Philipp S. Reif
Susanne Knake
Bernd A. Neubauer
Friedrich Zimprich
Martha Feucht
Eva M. Reinthaler
Wolfram S. Kunz
Gábor Zsurka
Rainer Surges
Tobias Baumgartner
Randi von Wrede
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 Müller-Schlüter
Gerhard Kluger
Martin Häusler
Ilan Blatt
Johannes R. Lemke
Ilona Krey
Yvonne G. Weber
Stefan Wolking
Felicitas Becker
Stephan Lauxmann
Christian Boßelmann
Josua Kegele
Christian Hengsbach
Sarah Rau
Bernhard J. Steinhoff
Andreas Schulze-Bonhage
Ingo Borggräfe
Christoph J. Schankin
Susanne Schubert-Bast
Herbert Schreiber
Thomas Mayer
Rudolf Korinthenberg
Knut Brockmann
Markus Wolff
Dieter Dennig
Rene Madeleyn
Reetta Kälviäinen
Anni Saarela
Oskari Timonen
Tarja Linnankivi
Anna-Elina Lehesjoki
Sylvain Rheims
Gaetan Lesca
Philippe Ryvlin
Louis Maillard
Luc Valton
Philippe Derambure
Fabrice Bartolomei
Edouard Hirsch
Véronique Michel
Francine Chassoux
Mark I. Rees
Seo-Kyung Chung
William O. Pickrell
Robert Powell
Mark D. Baker
Beata Fonferko-Shadrach
Charlotte Lawthom
Joseph Anderson
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
Norman Delanty
Colin P. Doherty
Arif Shukralla
Hany El-Naggar
Peter Widdess-Walsh
Nina Barišić
Laura Canafoglia
Silvana Franceschetti
Barbara Castellotti
Tiziana Granata
Francesca Ragona
Federico Zara
Michele Iacomino
Antonella Riva
Francesca Madia
Maria Stella Vari
Vincenzo Salpietro
Marcello Scala
Maria Margherita Mancardi
Lino Nobili
Elisabetta Amadori
Thea Giacomini
Francesca Bisulli
Tommaso Pippucci
Laura Licchetta
Raffaella Minardi
Paolo Tinuper
Lorenzo Muccioli
Barbara Mostacci
Antonio Gambardella
Angelo Labate
Grazia Annesi
Lorella Manna
Monica Gagliardi
Elena Parrini
Davide Mei
Annalisa Vetro
Claudia Bianchini
Martino Montomoli
Viola Doccini
Carmen Barba
Shinichi Hirose
Atsushi Ishii
Toshimitsu Suzuki
Yushi Inoue
Kazuhiro Yamakawa
Ahmad Beydoun
Wassim Nasreddine
Nathalie Khoueiry Zgheib
Birute Tumiene
Algirdas Utkus
Lynette G. Sadleir
Chontelle King
S. Hande Caglayan
Mutluay Arslan
Zuhal Yapıcı
Pınar Topaloglu
Bulent Kara
Uluc Yis
Dilsad Turkdogan
Aslı Gundogdu-Eken
Nerses Bebek
Sibel Uğur-İşeri
Betül Baykan
Barış Salman
Garen Haryanyan
Emrah Yücesan
Yeşim Kesim
YeşÇiğdem Özkara
Meng-Han Tsai
Chen-Jui Ho
Chih-Hsiang Lin
Kuang-Lin Lin
I-Jun Chou
Annapurna Poduri
Beth R. Shiedley
Catherine Shain
Jeffrey L. Noebels
Alicia Goldman
Robyn M. Busch
Lara Jehi
Imad M. Najm
Lisa Ferguson
Jean Khoury
Tracy A. Glauser
Peggy O. Clark
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
David A. Greenberg
Colin A. Ellis
Ethan Goldberg
Katherine L. Helbig
Mahgenn Cosico
Priya Vaidiswaran
Eryn Fitch
Samuel F. Berkovic
Holger Lerche
Daniel H. Lowenstein
David B. Goldstein
format Journal article
container_title The American Journal of Human Genetics
container_volume 108
container_issue 6
container_start_page 965
publishDate 2021
institution Swansea University
issn 0002-9297
doi_str_mv 10.1016/j.ajhg.2021.04.009
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
published_date 2021-06-03T20:22:26Z
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