Journal article 706 views
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
Full text not available from this repository: check for access using links below.
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...
| Published in: | The American Journal of Human Genetics |
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| ISSN: | 0002-9297 |
| Published: |
Elsevier BV
2021
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa60620 |
| 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. |
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| Keywords: |
epilepsy; epileptic encephalopathy; seizures; whole-exome sequencing; focal epilepsy; generalized epilepsy; intolerance; ClinVar; Epi25; Louvain |
| College: |
Faculty of Medicine, Health and Life Sciences |
| 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. |
| Issue: |
6 |
| Start Page: |
965 |
| End Page: |
982 |