Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals
Authors:   Epi25 Collaborative, Feng Yen-Chen Anne , Howrigan Daniel P. , Abbott Liam E. , Tashman Katherine , Cerrato Felecia , Singh Tarjinder , Heyne Henrike , Byrnes Andrea , Churchhouse Claire , Lal Dennis , Heinzen Erin L. , Cavalleri Gianpiero L. , Hakonarson Hakon , Helbig Ingo , Krause Roland , May Patrick , 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 , 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. ,   Cohort (GPC) Consortium Genomic Psychiatry, 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. 
Published: January 2019

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 variants 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 among 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 for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.