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Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Robert Powell, 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, Slavé 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 Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen 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 Müller-Schlüter, Gerhard Kluger, Martin Häusler, 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 Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Gerhard Kurlemann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, 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 Barišić, 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 Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, 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, Owen Pickrell Orcid Logo

The American Journal of Human Genetics, Volume: 105, Issue: 2, Pages: 267 - 282

Swansea University Authors: Robert Powell, Owen Pickrell Orcid Logo

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DOI (Published version): 10.1016/j.ajhg.2019.05.020

Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES...

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Published in: The American Journal of Human Genetics
ISSN: 0002-9297
Published: Elsevier BV 2019
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa51398
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2019-09-24T13:48:51.8763172</datestamp><bib-version>v2</bib-version><id>51398</id><entry>2019-08-15</entry><title>Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals</title><swanseaauthors><author><sid>7c8ac48bb6ae4281930e4138f94a51b6</sid><firstname>Robert</firstname><surname>Powell</surname><name>Robert Powell</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>1c3044b5ff7a6552ff5e8c9e3901c807</sid><ORCID>0000-0003-4396-5657</ORCID><firstname>Owen</firstname><surname>Pickrell</surname><name>Owen Pickrell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2019-08-15</date><deptcode>FGMHL</deptcode><abstract>Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of 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, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense burden across all three classes of epilepsy, while 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 DEE and GGE. Although no single gene surpassed exome-wide significance for individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role of GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.</abstract><type>Journal Article</type><journal>The American Journal of Human Genetics</journal><volume>105</volume><journalNumber>2</journalNumber><paginationStart>267</paginationStart><paginationEnd>282</paginationEnd><publisher>Elsevier BV</publisher><issnPrint>0002-9297</issnPrint><keywords>epilepsy; seizures; epileptic encephalopathy; exome; sequencing; burden analysis</keywords><publishedDay>1</publishedDay><publishedMonth>8</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-08-01</publishedDate><doi>10.1016/j.ajhg.2019.05.020</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine, Health and Life Science - Faculty</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>FGMHL</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2019-09-24T13:48:51.8763172</lastEdited><Created>2019-08-15T09:35:39.5785538</Created><authors><author><firstname>Robert</firstname><surname>Powell</surname><order>1</order></author><author><firstname>Yen-Chen Anne</firstname><surname>Feng</surname><order>2</order></author><author><firstname>Daniel P.</firstname><surname>Howrigan</surname><order>3</order></author><author><firstname>Liam E.</firstname><surname>Abbott</surname><order>4</order></author><author><firstname>Katherine</firstname><surname>Tashman</surname><order>5</order></author><author><firstname>Felecia</firstname><surname>Cerrato</surname><order>6</order></author><author><firstname>Tarjinder</firstname><surname>Singh</surname><order>7</order></author><author><firstname>Henrike</firstname><surname>Heyne</surname><order>8</order></author><author><firstname>Andrea</firstname><surname>Byrnes</surname><order>9</order></author><author><firstname>Claire</firstname><surname>Churchhouse</surname><order>10</order></author><author><firstname>Nick</firstname><surname>Watts</surname><order>11</order></author><author><firstname>Matthew</firstname><surname>Solomonson</surname><order>12</order></author><author><firstname>Dennis</firstname><surname>Lal</surname><order>13</order></author><author><firstname>Erin L.</firstname><surname>Heinzen</surname><order>14</order></author><author><firstname>Ryan S.</firstname><surname>Dhindsa</surname><order>15</order></author><author><firstname>Kate E.</firstname><surname>Stanley</surname><order>16</order></author><author><firstname>Gianpiero L.</firstname><surname>Cavalleri</surname><order>17</order></author><author><firstname>Hakon</firstname><surname>Hakonarson</surname><order>18</order></author><author><firstname>Ingo</firstname><surname>Helbig</surname><order>19</order></author><author><firstname>Roland</firstname><surname>Krause</surname><order>20</order></author><author><firstname>Patrick</firstname><surname>May</surname><order>21</order></author><author><firstname>Sarah</firstname><surname>Weckhuysen</surname><order>22</order></author><author><firstname>Slav&#xE9;</firstname><surname>Petrovski</surname><order>23</order></author><author><firstname>Sitharthan</firstname><surname>Kamalakaran</surname><order>24</order></author><author><firstname>Sanjay 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spelling 2019-09-24T13:48:51.8763172 v2 51398 2019-08-15 Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals 7c8ac48bb6ae4281930e4138f94a51b6 Robert Powell Robert Powell true false 1c3044b5ff7a6552ff5e8c9e3901c807 0000-0003-4396-5657 Owen Pickrell Owen Pickrell true false 2019-08-15 FGMHL Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of 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, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense burden across all three classes of epilepsy, while 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 DEE and GGE. Although no single gene surpassed exome-wide significance for individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role of GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date. Journal Article The American Journal of Human Genetics 105 2 267 282 Elsevier BV 0002-9297 epilepsy; seizures; epileptic encephalopathy; exome; sequencing; burden analysis 1 8 2019 2019-08-01 10.1016/j.ajhg.2019.05.020 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2019-09-24T13:48:51.8763172 2019-08-15T09:35:39.5785538 Robert Powell 1 Yen-Chen Anne Feng 2 Daniel P. Howrigan 3 Liam E. Abbott 4 Katherine Tashman 5 Felecia Cerrato 6 Tarjinder Singh 7 Henrike Heyne 8 Andrea Byrnes 9 Claire Churchhouse 10 Nick Watts 11 Matthew Solomonson 12 Dennis Lal 13 Erin L. Heinzen 14 Ryan S. Dhindsa 15 Kate E. Stanley 16 Gianpiero L. Cavalleri 17 Hakon Hakonarson 18 Ingo Helbig 19 Roland Krause 20 Patrick May 21 Sarah Weckhuysen 22 Slavé Petrovski 23 Sitharthan Kamalakaran 24 Sanjay M. Sisodiya 25 Patrick Cossette 26 Chris Cotsapas 27 Peter De Jonghe 28 Tracy Dixon-Salazar 29 Renzo Guerrini 30 Patrick Kwan 31 Anthony G. Marson 32 Randy Stewart 33 Chantal Depondt 34 Dennis J. Dlugos 35 Ingrid E. Scheffer 36 Pasquale Striano 37 Catharine Freyer 38 Kevin McKenna 39 Brigid M. Regan 40 Susannah T. Bellows 41 Costin Leu 42 Caitlin A. Bennett 43 Esther M.C. Johns 44 Alexandra Macdonald 45 Hannah Shilling 46 Rosemary Burgess 47 Dorien Weckhuysen 48 Melanie Bahlo 49 Terence J. O’Brien 50 Marian Todaro 51 Hannah Stamberger 52 Danielle M. Andrade 53 Tara R. Sadoway 54 Kelly Mo 55 Heinz Krestel 56 Sabina Gallati 57 Savvas S. Papacostas 58 Ioanna Kousiappa 59 George A. Tanteles 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 Wolfram S. Kunz 69 Gábor Zsurka 70 Christian E. Elger 71 Jürgen Bauer 72 Michael Rademacher 73 Manuela Pendziwiat 74 Hiltrud Muhle 75 Annika Rademacher 76 Andreas van Baalen 77 Sarah von Spiczak 78 Ulrich Stephani 79 Zaid Afawi 80 Amos D. Korczyn 81 Moien Kanaan 82 Christina Canavati 83 Gerhard Kurlemann 84 Karen Müller-Schlüter 85 Gerhard Kluger 86 Martin Häusler 87 Ilan Blatt 88 Johannes R. Lemke 89 Ilona Krey 90 Yvonne G. Weber 91 Stefan Wolking 92 Felicitas Becker 93 Christian Hengsbach 94 Sarah Rau 95 Ana F. Maisch 96 Bernhard J. Steinhoff 97 Andreas Schulze-Bonhage 98 Susanne Schubert-Bast 99 Herbert Schreiber 100 Ingo Borggräfe 101 Christoph J. Schankin 102 Thomas Mayer 103 Rudolf Korinthenberg 104 Knut Brockmann 105 Gerhard Kurlemann 106 Dieter Dennig 107 Rene Madeleyn 108 Reetta Kälviäinen 109 Pia Auvinen 110 Anni Saarela 111 Tarja Linnankivi 112 Anna-Elina Lehesjoki 113 Mark I. Rees 114 Seo-Kyung Chung 115 William O. Pickrell 116 Robert Powell 117 Natascha Schneider 118 Simona Balestrini 119 Sara Zagaglia 120 Vera Braatz 121 Michael R. Johnson 122 Pauls Auce 123 Graeme J. Sills 124 Larry W. Baum 125 Pak C. Sham 126 Stacey S. Cherny 127 Colin H.T. Lui 128 Nina Barišić 129 Norman Delanty 130 Colin P. Doherty 131 Arif Shukralla 132 Mark McCormack 133 Hany El-Naggar 134 Laura Canafoglia 135 Silvana Franceschetti 136 Barbara Castellotti 137 Tiziana Granata 138 Federico Zara 139 Michele Iacomino 140 Francesca Madia 141 Maria Stella Vari 142 Maria Margherita Mancardi 143 Vincenzo Salpietro 144 Francesca Bisulli 145 Paolo Tinuper 146 Laura Licchetta 147 Tommaso Pippucci 148 Carlotta Stipa 149 Raffaella Minardi 150 Antonio Gambardella 151 Angelo Labate 152 Grazia Annesi 153 Lorella Manna 154 Monica Gagliardi 155 Elena Parrini 156 Davide Mei 157 Annalisa Vetro 158 Claudia Bianchini 159 Martino Montomoli 160 Viola Doccini 161 Carla Marini 162 Toshimitsu Suzuki 163 Yushi Inoue 164 Kazuhiro Yamakawa 165 Birute Tumiene 166 Lynette G. Sadleir 167 Chontelle King 168 Emily Mountier 169 S. Hande Caglayan 170 Mutluay Arslan 171 Zuhal Yapıcı 172 Uluc Yis 173 Pınar Topaloglu 174 Bulent Kara 175 Dilsad Turkdogan 176 Aslı Gundogdu-Eken 177 Nerses Bebek 178 Sibel Uğur-İşeri 179 Betül Baykan 180 Barış Salman 181 Garen Haryanyan 182 Emrah Yücesan 183 Yeşim Kesim 184 Çiğdem Özkara 185 Annapurna Poduri 186 Beth R. Shiedley 187 Catherine Shain 188 Russell J. Buono 189 Thomas N. Ferraro 190 Michael R. Sperling 191 Warren Lo 192 Michael Privitera 193 Jacqueline A. French 194 Steven Schachter 195 Ruben I. Kuzniecky 196 Orrin Devinsky 197 Manu Hegde 198 Pouya Khankhanian 199 Katherine L. Helbig 200 Colin A. Ellis 201 Gianfranco Spalletta 202 Fabrizio Piras 203 Federica Piras 204 Tommaso Gili 205 Valentina Ciullo 206 Andreas Reif 207 Andrew McQuillin 208 Nick Bass 209 Andrew McIntosh 210 Douglas Blackwood 211 Mandy Johnstone 212 Aarno Palotie 213 Michele T. Pato 214 Carlos N. Pato 215 Evelyn J. Bromet 216 Celia Barreto Carvalho 217 Eric D. Achtyes 218 Maria Helena Azevedo 219 Roman Kotov 220 Douglas S. Lehrer 221 Dolores Malaspina 222 Stephen R. Marder 223 Helena Medeiros 224 Christopher P. Morley 225 Diana O. Perkins 226 Janet L. Sobell 227 Peter F. Buckley 228 Fabio Macciardi 229 Mark H. Rapaport 230 James A. Knowles 231 Ayman H. Fanous 232 Steven A. McCarroll 233 Namrata Gupta 234 Stacey B. Gabriel 235 Mark J. Daly 236 Eric S. Lander 237 Daniel H. Lowenstein 238 David B. Goldstein 239 Holger Lerche 240 Samuel F. Berkovic 241 Benjamin M. Neale 242 Owen Pickrell 0000-0003-4396-5657 243 51398__15710__c52ca83e489c49e7a8d471c1ab7659ff.pdf Epi25_Preprint.pdf 2019-10-24T09:05:50.1806108 Output 489399 application/pdf Author's Original true Released under the terms of a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND). true
title Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
spellingShingle Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Robert Powell
Owen Pickrell
title_short Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
title_full Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
title_fullStr Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
title_full_unstemmed Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
title_sort Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
author_id_str_mv 7c8ac48bb6ae4281930e4138f94a51b6
1c3044b5ff7a6552ff5e8c9e3901c807
author_id_fullname_str_mv 7c8ac48bb6ae4281930e4138f94a51b6_***_Robert Powell
1c3044b5ff7a6552ff5e8c9e3901c807_***_Owen Pickrell
author Robert Powell
Owen Pickrell
author2 Robert Powell
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
Slavé 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 Štěrbová
Markéta Vlčková
Lucie Sedláčková
Petra Laššuthová
Karl Martin Klein
Felix Rosenow
Philipp S. Reif
Susanne Knake
Wolfram S. Kunz
Gábor Zsurka
Christian E. Elger
Jürgen 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 Müller-Schlüter
Gerhard Kluger
Martin Häusler
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 Borggräfe
Christoph J. Schankin
Thomas Mayer
Rudolf Korinthenberg
Knut Brockmann
Gerhard Kurlemann
Dieter Dennig
Rene Madeleyn
Reetta Kälviäinen
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 Barišić
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 Yapıcı
Uluc Yis
Pınar Topaloglu
Bulent Kara
Dilsad Turkdogan
Aslı Gundogdu-Eken
Nerses Bebek
Sibel Uğur-İşeri
Betül Baykan
Barış Salman
Garen Haryanyan
Emrah Yücesan
Yeşim Kesim
Çiğdem Özkara
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
Owen Pickrell
format Journal article
container_title The American Journal of Human Genetics
container_volume 105
container_issue 2
container_start_page 267
publishDate 2019
institution Swansea University
issn 0002-9297
doi_str_mv 10.1016/j.ajhg.2019.05.020
publisher Elsevier BV
document_store_str 1
active_str 0
description Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of 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, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense burden across all three classes of epilepsy, while 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 DEE and GGE. Although no single gene surpassed exome-wide significance for individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role of GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
published_date 2019-08-01T04:03:16Z
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score 11.01306

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