Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
Authors: Montanucci Ludovica , Lewis-Smith David , Collins Ryan L. , Niestroj Lisa-Marie , Parthasarathy Shridhar , Xian Julie , Ganesan Shiva , Macnee Marie , Brünger Tobias , Thomas Rhys H. , Talkowski Michael ,   Epi25 Collaborative,   Columbia University Institute for Genomic Medicine analysis group, Motelow Joshua E. , Povysil Gundula , Dhindsa Ryan S. , Stanley Kate E. , Allen Andrew S. , Goldstein David B. ,   Epi25 sequencing, analysis, project management, and browser development at the Broad Institute, 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. ,   Epi25 executive committee, Berkovic Samuel F. , Lerche Holger , Lowenstein Daniel H. ,   Epi25 strategy, phenotyping, analysis, informatics, and project management committees, Cavalleri Gianpiero L. , Cossette Patrick , Cotsapas Chris , De Jonghe Peter , 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 , May Patrick , McKenna Kevin , Regan Brigid M. , Bennett Caitlin A. , Leech Stephanie L. , Leu Costin , Lewis-Smith David ,   Authors from individual Epi25 cohorts:,   Australia: Melbourne (AUSAUS),   Australia: Royal Melbourne (AUSRMB), O’Brien Terence J. , Todaro Marian ,   Belgium: Antwerp (BELATW), Stamberger Hannah ,   Belgium: Brussels (BELULB), Depondti Chantal ,   Canada: Andrade (CANUTN), Andrade Danielle M. , Ali Quratulain Zulfiqar , Sadoway Tara R. ,   Switzerland: Bern (CHEUBB), Krestel Heinz , Schaller André ,   Cyprus (CYPCYP), Papacostas Savvas S. , Kousiappa Ioanna , Tanteles George A. , Yiolanda Christou ,   Czech Republic: Prague (CZEMTH), Štěrbová Katalin , Vlčková Markéta , Sedláčková Lucie , Laššuthová Petra ,   Germany: Frankfurt/Marburg (DEUPUM), Klein Karl Martin , Rosenow Felix , Reif Philipp S. , Knake Susanne ,   Germany: Giessen (DEUUGS), Neubauer Bernd A. , Zimprich Friedrich , Feucht Martha , Reinthaler Eva ,   Germany: Bonn (DEUUKB), Kunz Wolfram S. , Zsurka Gábor , Surges Rainer , Baumgartner Tobias H. , von Wrede Randi ,   Germany: Kiel (DEUUKL), Helbig Ingo , Pendziwiat Manuela , Muhle Hiltrud , Rademacher Annika , van Baalen Andreas , von Spiczak Sarah , Stephani Ulrich , Afawi Zaid , Korczyn Amos D. , Kanaan Moien , Canavati Christina , Kurlemann Gerhard , Müller-Schlüter Karen , Kluger Gerhard , Häusler Martin , Blatt Ilan ,   Germany: Leipzig (DEUULG), Lemke Johannes R. , Krey Ilona ,   Germany: Tuebingen (DEUUTB), 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 , Kurlemann Gerhard , Dennig Dieter , Madeleyn Rene ,   Finland: Kuopio (FINKPH), Kälviäinen Reetta , Saarela Anni , Timonen Oskari ,   Finland: Helsinki (FINUVH), Linnankivi Tarja , Lehesjoki Anna-Elina ,   France: Lyon (FRALYU), Rheims Sylvain , Lesca Gaetan , Ryvlin Philippe , Maillard Louis , Valton Luc , Derambure Philippe , Bartolomei Fabrice , Hirsch Edouard , Michel Véronique , Chassoux Francine ,   Wales: Swansea (GBRSWU), Rees Mark I. , Chung Seo-Kyung , Pickrell William O. , Powell Robert H. W. , Baker Mark D. , Fonferko-Shadrach Beata , Lawthom Charlotte , Anderson Joe ,   UK: UCL (GBRUCL), Schneider Natascha , Balestrini Simona , Zagaglia Sara , Braatz Vera ,   UK: Imperial/Liverpool (GBRUNL), Johnson Michael R. , Auce Pauls , Sills Graeme J. ,   Hong Kong (HKGHKK), Kwan Patrick , Baum Larry W. , Sham Pak C. , Cherny Stacey S. , Lui Colin H. T. ,   Ireland: Dublin (IRLRCI), Delanty Norman , Doherty Colin P. , Shukralla Arif , El-Naggar Hany , Widdess-Walsh Peter ,   Croatia (HRVUZG), Barišić Nina ,   Italy: Milan (ITAICB), Canafoglia Laura , Franceschetti Silvana , Castellotti Barbara , Granata Tiziana , Ragona Francesca ,   Italy: Genova (ITAIGI), Zara Federico , Iacomino Michele , Riva Antonella , Madia Francesca , Vari Maria Stella , Salpietro Vincenzo , Scala Marcello , Mancardi Maria Margherita , Lino Nobili , Amadori Elisa , Giacomini Thea ,   Italy: Bologna (ITAUBG), Bisulli Francesca , Pippucci Tommaso , Licchetta Laura , Minardi Raffaella , Tinuper Paolo , Muccioli Lorenzo , Mostacci Barbara ,   Italy: Catanzaro (ITAUMC), Gambardella Antonio , Labate Angelo , Annesi Grazia , Manna Lorella , Gagliardi Monica ,   Italy: Florence (ITAUMR), Parrini Elena , Mei Davide , Vetro Annalisa , Bianchini Claudia , Montomoli Martino , Doccini Viola , Barba Carmen ,   Japan: Fukuoka (JPNFKA), Hirose Shinichi , Ishii Atsushi ,   Japan: RIKEN Institute (JPNRKI), Suzuki Toshimitsu , Inoue Yushi , Yamakawa Kazuhiro ,   Lebanon: Beirut (LEBABM), Beydoun Ahmad , Nasreddine Wassim , Khoueiry-Zgheib Nathalie ,   Lithuania (LTUUHK), Tumiene Birute , Utkus Algirdas ,   New Zealand: Otago (NZLUTO), Sadleir Lynette G. , King Chontelle ,   Turkey: Bogazici (TURBZU), Caglayan S. Hande , Arslan Mutluay , Yapıcı Zuhal , Topaloglu Pınar , Kara Bulent , Yis Uluc , Turkdogan Dilsad , Gundogdu-Eken Aslı ,   Turkey: Istanbul (TURIBU), Bebek Nerses , Uğur-İşeri Sibel , Baykan Betül , Salman Barış , Haryanyan Garen , Yücesan Emrah , Kesim Yeşim , Özkara Çiğdem ,   Taiwan (TWNCGM), Tsai Meng-Han , Ho Chen-Jui , Lin Chih-Hsiang , Lin Kuang-Lin , Chou I-Jun ,   USA: BCH (USABCH), Poduri Annapurna , Shiedley Beth R. , Shain Catherine ,   USA: Baylor College of Medicine (USABLC), Noebels Jeffrey L. , Goldman Alicia ,   USA: Cleveland Clinic (USACCF), Busch Robyn M. , Jehi Lara , Najm Imad M. , Lal Dennis , Ferguson Lisa , Khoury Jean ,   USA: Cincinnati Children’s Hospital Medical Center (USACCH), Glauser Tracy A. , Clark Peggy O. ,   USA: Philadelphia/CHOP (USACHP) and Philadelphia/Rowan (USACRW), Buono Russell J. , Ferraro Thomas N. , Sperling Michael R. , Dlugos Dennis J. , Lo Warren , Privitera Michael , French Jacqueline A. , Schachter Steven ,   USA: EPGP (USAEGP), Kuzniecky Ruben I. , Devinsky Orrin ,   USA: NYU HEP (USAHEP), Hegde Manu ,   USA: Nationwide Children’s Hospital (USANCH), Greenberg David A. ,   USA: Penn/CHOP (USAUPN), Ellis Colin A. , Goldberg Ethan , Helbig Katherine L. , Cosico Mahgenn , Vaidiswaran Priya , Fitch Eryn ,   Kenya: Kilifi; South Africa: Aguincourt; Ghana: Kintampo (KENKIL, GHAKNT, ZAFAGN), Newton Charles R. J. C. , Kariuki Symon M. , Wagner Ryan G. , Owusu-Agyei Seth ,   USA: Massachusetts General Hospital (USAMGH), Cole Andrew J. , McGraw Christopher M. , Siena S. Anthony ,   USA: Vanderbilt University Medical Centre (USAVAN), Davis Lea , Hucks Donald , Faucon Annika , Wu David , Abou-Khalil Bassel W. , Haas Kevin , Taneja Randip S. , Helbig Ingo , Leu Costin , Lal Dennis 
Published: July 2023

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.