Article (Scientific journals)
Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
Motelow, Joshua E.; Povysil, Gundula; Dhindsa, Ryan S. et al.
2021In The American Journal of Human Genetics
Peer reviewed
 

Files


Full Text
Subgenic intolerance Epi25.pdf
Publisher postprint (2.56 MB)
Request a copy

All documents in ORBilu are protected by a user license.

Send to



Details



Keywords :
epilepsy; epileptic encephalopathy; seizures; whole-exome sequencing; focal epilepsy; generalized epilepsy; intolerance; ClinVar; Epi25; Louvain
Abstract :
[en] Summary 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Motelow, Joshua E.
Povysil, Gundula
Dhindsa, Ryan S.
Stanley, Kate E.
Allen, Andrew S.
Feng, Yen-Chen Anne
Howrigan, Daniel P.
Abbott, Liam E.
Tashman, Katherine
Cerrato, Felecia
Cusick, Caroline
Singh, Tarjinder
Heyne, Henrike
Byrnes, Andrea E.
Churchhouse, Claire
Watts, Nick
Solomonson, Matthew
Lal, Dennis
Gupta, Namrata
Neale, Benjamin M.
Cavalleri, Gianpiero L.
Cossette, Patrick
Cotsapas, Chris
Jonghe, Peter De
Dixon-Salazar, Tracy
Guerrini, Renzo
Hakonarson, Hakon
Heinzen, Erin L.
Helbig, Ingo
Kwan, Patrick
Marson, Anthony G.
Petrovski, Slavé
Kamalakaran, Sitharthan
Sisodiya, Sanjay M.
Stewart, Randy
Weckhuysen, Sarah
Depondt, Chantal
Dlugos, Dennis J.
Scheffer, Ingrid E.
Striano, Pasquale
Freyer, Catharine
Krause, Roland  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
McKenna, Kevin
Regan, Brigid M.
Bennett, Caitlin A.
Leu, Costin
Leech, Stephanie L.
O’Brien, Terence J.
Todaro, Marian
Stamberger, Hannah
Andrade, Danielle M.
Ali, Quratulain Zulfiqar
Sadoway, Tara R.
Krestel, Heinz
Schaller, André
Papacostas, Savvas S.
Kousiappa, Ioanna
Tanteles, George A.
Christou, Yiolanda
Štěrbová, Katalin
Vlčková, Markéta
Sedláčková, Lucie
Laššuthová, Petra
Klein, Karl Martin
Rosenow, Felix
Reif, Philipp S.
Knake, Susanne
Neubauer, Bernd A.
Zimprich, Friedrich
Feucht, Martha
Reinthaler, Eva M.
Kunz, Wolfram S.
Zsurka, Gábor
Surges, Rainer
Baumgartner, Tobias
Wrede, Randi Von
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
Lauxmann, Stephan
Boßelmann, Christian
Kegele, Josua
Hengsbach, Christian
Rau, Sarah
Steinhoff, Bernhard J.
Schulze-Bonhage, Andreas
Borggräfe, Ingo
Schankin, Christoph J.
Schubert-Bast, Susanne
Schreiber, Herbert
Mayer, Thomas
Korinthenberg, Rudolf
Brockmann, Knut
Wolff, Markus
Dennig, Dieter
Madeleyn, Rene
Kälviäinen, Reetta
Saarela, Anni
Timonen, Oskari
Linnankivi, Tarja
Lehesjoki, Anna-Elina
Rheims, Sylvain
Lesca, Gaetan
Ryvlin, Philippe
Maillard, Louis
Valton, Luc
Derambure, Philippe
Bartolomei, Fabrice
Hirsch, Edouard
Michel, Véronique
Chassoux, Francine
Rees, Mark I.
Chung, Seo-Kyung
Pickrell, William O.
Powell, Robert
Baker, Mark D.
Fonferko-Shadrach, Beata
Lawthom, Charlotte
Anderson, Joseph
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.
Delanty, Norman
Doherty, Colin P.
Shukralla, Arif
El-Naggar, Hany
Widdess-Walsh, Peter
Barišić, Nina
Canafoglia, Laura
Franceschetti, Silvana
Castellotti, Barbara
Granata, Tiziana
Ragona, Francesca
Zara, Federico
Iacomino, Michele
Riva, Antonella
Madia, Francesca
Vari, Maria Stella
Salpietro, Vincenzo
Scala, Marcello
Mancardi, Maria Margherita
Nobili, Lino
Amadori, Elisabetta
Giacomini, Thea
Bisulli, Francesca
Pippucci, Tommaso
Licchetta, Laura
Minardi, Raffaella
Tinuper, Paolo
Muccioli, Lorenzo
Mostacci, Barbara
Gambardella, Antonio
Labate, Angelo
Annesi, Grazia
Manna, Lorella
Gagliardi, Monica
Parrini, Elena
Mei, Davide
Vetro, Annalisa
Bianchini, Claudia
Montomoli, Martino
Doccini, Viola
Barba, Carmen
Hirose, Shinichi
Ishii, Atsushi
Suzuki, Toshimitsu
Inoue, Yushi
Yamakawa, Kazuhiro
Beydoun, Ahmad
Nasreddine, Wassim
Zgheib, Nathalie Khoueiry
Tumiene, Birute
Utkus, Algirdas
Sadleir, Lynette G.
King, Chontelle
Caglayan, S. Hande
Arslan, Mutluay
Yapıcı, Zuhal
Topaloglu, Pınar
Kara, Bulent
Yis, Uluc
Turkdogan, Dilsad
Gundogdu-Eken, Aslı
Bebek, Nerses
Tsai, Meng-Han
Ho, Chen-Jui
Lin, Chih-Hsiang
Lin, Kuang-Lin
Chou, I.-Jun
Poduri, Annapurna
Shiedley, Beth R.
Shain, Catherine
Noebels, Jeffrey L.
Goldman, Alicia
Busch, Robyn M.
Jehi, Lara
Najm, Imad M.
Ferguson, Lisa
Khoury, Jean
Glauser, Tracy A.
Clark, Peggy O.
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
Greenberg, David A.
Ellis, Colin A.
Goldberg, Ethan
Helbig, Katherine L.
Cosico, Mahgenn
Vaidiswaran, Priya
Fitch, Eryn
Berkovic, Samuel F.
Lerche, Holger
Lowenstein, Daniel H.
Goldstein, David B.
More authors (238 more) Less
External co-authors :
yes
Language :
English
Title :
Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
Publication date :
30 April 2021
Journal title :
The American Journal of Human Genetics
ISSN :
0002-9297
Peer reviewed :
Peer reviewed
Focus Area :
Systems Biomedicine
FnR Project :
FNR11583046 - Epileptogenesis Of Genetic Epilepsies, 2017 (01/04/2018-30/06/2021) - Roland Krause
Available on ORBilu :
since 03 May 2021

Statistics


Number of views
94 (4 by Unilu)
Number of downloads
0 (0 by Unilu)

Scopus citations®
 
26
Scopus citations®
without self-citations
14
OpenCitations
 
16
WoS citations
 
28

Bibliography


Similar publications



Contact ORBilu