RT Journal Article
SR Electronic
T1 Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 525683
DO 10.1101/525683
A1 Epi25 Collaborative
A1 Yen-Chen Anne Feng
A1 Daniel P. Howrigan
A1 Liam E. Abbott
A1 Katherine Tashman
A1 Felecia Cerrato
A1 Tarjinder Singh
A1 Henrike Heyne
A1 Andrea Byrnes
A1 Claire Churchhouse
A1 Dennis Lal
A1 Erin L. Heinzen
A1 Gianpiero L. Cavalleri
A1 Hakon Hakonarson
A1 Ingo Helbig
A1 Roland Krause
A1 Patrick May
A1 Sarah Weckhuysen
A1 Slavé Petrovski
A1 Sitharthan Kamalakaran
A1 Sanjay M. Sisodiya
A1 Patrick Cossette
A1 Chris Cotsapas
A1 Peter De Jonghe
A1 Tracy Dixon-Salazar
A1 Renzo Guerrini
A1 Patrick Kwan
A1 Anthony G. Marson
A1 Randy Stewart
A1 Chantal Depondt
A1 Dennis J. Dlugos
A1 Ingrid E. Scheffer
A1 Pasquale Striano
A1 Catharine Freyer
A1 Kevin McKenna
A1 Brigid M. Regan
A1 Susannah T. Bellows
A1 Costin Leu
A1 Caitlin A. Bennett
A1 Esther M.C. Johns
A1 Alexandra Macdonald
A1 Hannah Shilling
A1 Rosemary Burgess
A1 Dorien Weckhuysen
A1 Melanie Bahlo
A1 Terence J. O’Brien
A1 Marian Todaro
A1 Hannah Stamberger
A1 Danielle M. Andrade
A1 Tara R. Sadoway
A1 Kelly Mo
A1 Heinz Krestel
A1 Sabina Gallati
A1 Savvas S. Papacostas
A1 Ioanna Kousiappa
A1 George A. Tanteles
A1 Katalin Štěrbová
A1 Markéta Vlčková
A1 Lucie Sedláčková
A1 Petra Laššuthová
A1 Karl Martin Klein
A1 Felix Rosenow
A1 Philipp S. Reif
A1 Susanne Knake
A1 Wolfram S. Kunz
A1 Gábor Zsurka
A1 Christian E. Elger
A1 Jürgen Bauer
A1 Michael Rademacher
A1 Manuela Pendziwiat
A1 Hiltrud Muhle
A1 Annika Rademacher
A1 Andreas van Baalen
A1 Sarah von Spiczak
A1 Ulrich Stephani
A1 Zaid Afawi
A1 Amos D. Korczyn
A1 Moien Kanaan
A1 Christina Canavati
A1 Gerhard Kurlemann
A1 Karen Müller-Schlüter
A1 Gerhard Kluger
A1 Martin Häusler
A1 Ilan Blatt
A1 Johannes R. Lemke
A1 Ilona Krey
A1 Yvonne G. Weber
A1 Stefan Wolking
A1 Felicitas Becker
A1 Christian Hengsbach
A1 Sarah Rau
A1 Ana F. Maisch
A1 Bernhard J. Steinhoff
A1 Andreas Schulze-Bonhage
A1 Susanne Schubert-Bast
A1 Herbert Schreiber
A1 Ingo Borggräfe
A1 Christoph J. Schankin
A1 Thomas Mayer
A1 Rudolf Korinthenberg
A1 Knut Brockmann
A1 Gerhard Kurlemann
A1 Dieter Dennig
A1 Rene Madeleyn
A1 Reetta Kälviäinen
A1 Pia Auvinen
A1 Anni Saarela
A1 Tarja Linnankivi
A1 Anna-Elina Lehesjoki
A1 Mark I. Rees
A1 Seo-Kyung Chung
A1 William O. Pickrell
A1 Robert Powell
A1 Natascha Schneider
A1 Simona Balestrini
A1 Sara Zagaglia
A1 Vera Braatz
A1 Michael R. Johnson
A1 Pauls Auce
A1 Graeme J. Sills
A1 Larry W. Baum
A1 Pak C. Sham
A1 Stacey S. Cherny
A1 Colin H.T. Lui
A1 Nina Barišić
A1 Norman Delanty
A1 Colin P. Doherty
A1 Arif Shukralla
A1 Mark McCormack
A1 Hany El-Naggar
A1 Laura Canafoglia
A1 Silvana Franceschetti
A1 Barbara Castellotti
A1 Tiziana Granata
A1 Federico Zara
A1 Michele Iacomino
A1 Francesca Madia
A1 Maria Stella Vari
A1 Maria Margherita Mancardi
A1 Vincenzo Salpietro
A1 Francesca Bisulli
A1 Paolo Tinuper
A1 Laura Licchetta
A1 Tommaso Pippucci
A1 Carlotta Stipa
A1 Raffaella Minardi
A1 Antonio Gambardella
A1 Angelo Labate
A1 Grazia Annesi
A1 Lorella Manna
A1 Monica Gagliardi
A1 Elena Parrini
A1 Davide Mei
A1 Annalisa Vetro
A1 Claudia Bianchini
A1 Martino Montomoli
A1 Viola Doccini
A1 Carla Marini
A1 Toshimitsu Suzuki
A1 Yushi Inoue
A1 Kazuhiro Yamakawa
A1 Birute Tumiene
A1 Lynette G. Sadleir
A1 Chontelle King
A1 Emily Mountier
A1 S. Hande Caglayan
A1 Mutluay Arslan
A1 Zuhal Yapıcı
A1 Uluc Yis
A1 Pınar Topaloglu
A1 Bulent Kara
A1 Dilsad Turkdogan
A1 Aslı Gundogdu-Eken
A1 Nerses Bebek
A1 Sibel Uğur-İşeri
A1 Betül Baykan
A1 Barış Salman
A1 Garen Haryanyan
A1 Emrah Yücesan
A1 Yeşim Kesim
A1 Çiğdem Özkara
A1 Annapurna Poduri
A1 Russell J. Buono
A1 Thomas N. Ferraro
A1 Michael R. Sperling
A1 Warren Lo
A1 Michael Privitera
A1 Jacqueline A. French
A1 Steven Schachter
A1 Ruben I. Kuzniecky
A1 Orrin Devinsky
A1 Manu Hegde
A1 Pouya Khankhanian
A1 Katherine L. Helbig
A1 Colin A. Ellis
A1 Gianfranco Spalletta
A1 Fabrizio Piras
A1 Federica Piras
A1 Tommaso Gili
A1 Valentina Ciullo
A1 Andreas Reif
A1 Andrew McQuillin
A1 Nick Bass
A1 Andrew McIntosh
A1 Douglas Blackwood
A1 Mandy Johnstone
A1 Aarno Palotie
A1 Michele T. Pato
A1 Carlos N. Pato
A1 Evelyn J. Bromet
A1 Celia Barreto Carvalho
A1 Eric D. Achtyes
A1 Maria Helena Azevedo
A1 Roman Kotov
A1 Douglas S. Lehrer
A1 Dolores Malaspina
A1 Stephen R. Marder
A1 Helena Medeiros
A1 Christopher P. Morley
A1 Diana O. Perkins
A1 Janet L. Sobell
A1 Peter F. Buckley
A1 Fabio Macciardi
A1 Mark H. Rapaport
A1 James A. Knowles
A1 Cohort (GPC) Consortium Genomic Psychiatry
A1 Ayman H. Fanous
A1 Steven A. McCarroll
A1 Namrata Gupta
A1 Stacey B. Gabriel
A1 Mark J. Daly
A1 Eric S. Lander
A1 Daniel H. Lowenstein
A1 David B. Goldstein
A1 Holger Lerche
A1 Samuel F. Berkovic
A1 Benjamin M. Neale
YR 2019
UL http://biorxiv.org/content/early/2019/01/21/525683.abstract
AB 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.