Article (Scientific journals)
Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Feng, Yen-Chen Anne; Howrigan, Daniel P.; Abbott, Liam E. et al.
2019In American Journal of Human Genetics
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Keywords :
epilepsy; seizures; epileptic encephalopathy; exome; sequencing; burden analysis
Abstract :
[en] 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 GABAA 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-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  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Weckhuysen, Sarah
Petrovski, Slavé
Kamalakaran, Sitharthan
Sisodiya, Sanjay M.
Cossette, Patrick
Cotsapas, Chris
Jonghe, Peter De
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.
Štěrbová, Katalin
Vlčková, Markéta
Sedláčková, Lucie
Laššuthová, Petra
Klein, Karl Martin
Rosenow, Felix
Reif, Philipp S.
Knake, Susanne
Kunz, Wolfram S.
Zsurka, Gábor
Elger, Christian E.
Bauer, Jürgen
Rademacher, Michael
Pendziwiat, Manuela
Muhle, Hiltrud
Rademacher, Annika
Baalen, Andreas Van
Spiczak, Sarah Von
Stephani, Ulrich
Afawi, Zaid
Korczyn, Amos D.
Kanaan, Moien
Canavati, Christina
Kurlemann, Gerhard
Müller-Schlüter, Karen
Kluger, Gerhard
Häusler, 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
Borggräfe, Ingo
Schankin, Christoph J.
Mayer, Thomas
Korinthenberg, Rudolf
Brockmann, Knut
Kurlemann, Gerhard
Dennig, Dieter
Madeleyn, Rene
Kälviäinen, 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.
Barišić, 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
Yapıcı, Zuhal
Yis, Uluc
Topaloglu, Pınar
Kara, Bulent
Turkdogan, Dilsad
Gundogdu-Eken, Aslı
Bebek, Nerses
Uğur-İşeri, Sibel
Baykan, Betül
Salman, Barış
Haryanyan, Garen
Yücesan, Emrah
Kesim, Yeşim
Özkara, Çiğdem
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.
More authors (231 more) Less
External co-authors :
yes
Language :
English
Title :
Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Publication date :
18 July 2019
Journal title :
American Journal of Human Genetics
ISSN :
1537-6605
Publisher :
University of Chicago Press, Chicago, United States - Illinois
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 22 July 2019

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