Dataset Information

Shared and distinct ultra-rare genetic risk for diverse epilepsies: A whole-exome sequencing study of 54,423 individuals across multiple genetic ancestries.

ABSTRACT: Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date to investigate rare variants that confer risk for a spectrum of epilepsy syndromes. With an unprecedented sample size of >54,000 human exomes, composed of 20,979 deep-phenotyped patients with epilepsy and 33,444 controls, we replicate previous gene findings at exome-wide significance; using a hypothesis-free approach, we identify potential novel associations. Most discoveries are specific to a particular subtype of epilepsy, highlighting distinct genetic contributions to different epilepsies. Combining evidence from rare single nucleotide/short indel-, copy number-, and common variants, we find convergence of different genetic risk factors at the level of individual genes. Further comparing to other exome-sequencing studies, we implicate shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our study also demonstrates the value of collaborative sequencing and deep-phenotyping efforts, which will continue to unravel the complex genetic architecture underlying the heterogeneity of epilepsy.

SUBMITTER: Epi25 Collaborative

PROVIDER: S-EPMC9980234 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Chen Siwei S Abou-Khalil Bassel W BW Afawi Zaid Z Ali Quratulain Zulfiqar QZ Amadori Elisabetta E Anderson Alison A Anderson Joe J Andrade Danielle M DM Annesi Grazia G Arslan Mutluay M Auce Pauls P Bahlo Melanie M Baker Mark D MD Balagura Ganna G Balestrini Simona S Banks Eric E Barba Carmen C Barboza Karen K Bartolomei Fabrice F Bass Nick N Baum Larry W LW Baumgartner Tobias H TH Baykan Betül B Bebek Nerses N Becker Felicitas F Bennett Caitlin A CA Beydoun Ahmad A Bianchini Claudia C Bisulli Francesca F Blackwood Douglas D Blatt Ilan I Borggräfe Ingo I Bosselmann Christian C Braatz Vera V Brand Harrison H Brockmann Knut K Buono Russell J RJ Busch Robyn M RM Caglayan S Hande SH Canafoglia Laura L Canavati Christina C Castellotti Barbara B Cavalleri Gianpiero L GL Cerrato Felecia F Chassoux Francine F Cherian Christina C Cherny Stacey S SS Cheung Ching-Lung CL Chou I-Jun IJ Chung Seo-Kyung SK Churchhouse Claire C Ciullo Valentina V Clark Peggy O PO Cole Andrew J AJ Cosico Mahgenn M Cossette Patrick P Cotsapas Chris C Cusick Caroline C Daly Mark J MJ Davis Lea K LK Jonghe Peter De P Delanty Norman N Dennig Dieter D Depondt Chantal C Derambure Philippe P Devinsky Orrin O Di Vito Lidia L Dickerson Faith F Dlugos Dennis J DJ Doccini Viola V Doherty Colin P CP El-Naggar Hany H Ellis Colin A CA Epstein Leon L Evans Meghan M Faucon Annika A Feng Yen-Chen Anne YA Ferguson Lisa L Ferraro Thomas N TN Da Silva Izabela Ferreira IF Ferri Lorenzo L Feucht Martha M Fields Madeline C MC Fitzgerald Mark M Fonferko-Shadrach Beata B Fortunato Francesco F Franceschetti Silvana S French Jacqueline A JA Freri Elena E Fu Jack M JM Gabriel Stacey S Gagliardi Monica M Gambardella Antonio A Gauthier Laura L Giangregorio Tania T Gili Tommaso T Glauser Tracy A TA Goldberg Ethan E Goldman Alica A Goldstein David B DB Granata Tiziana T Grant Riley R Greenberg David A DA Guerrini Renzo R Gundogdu-Eken Aslı A Gupta Namrata N Haas Kevin K Hakonarson Hakon H Haryanyan Garen G Häusler Martin M Hegde Manu M Heinzen Erin L EL Helbig Ingo I Hengsbach Christian C Heyne Henrike H Hirose Shinichi S Hirsch Edouard E Ho Chen-Jui CJ Hoeper Olivia O Howrigan Daniel P DP Hucks Donald D Hung Po-Chen PC Iacomino Michele M Inoue Yushi Y Inuzuka Luciana Midori LM Ishii Atsushi A Jehi Lara L Johnson Michael R MR Johnstone Mandy M Kälviäinen Reetta R Kanaan Moien M Kara Bulent B Kariuki Symon M SM Kegele Josua J Kesim Yeşim Y Khoueiry-Zgheib Nathalie N Khoury Jean J King Chontelle C Klein Karl Martin KM Kluger Gerhard G Knake Susanne S Kok Fernando F Korczyn Amos D AD Korinthenberg Rudolf R Koupparis Andreas A Kousiappa Ioanna I Krause Roland R Krenn Martin M Krestel Heinz H Krey Ilona I Kunz Wolfram S WS Kurlemann Gerhard G Kuzniecky Ruben I RI Kwan Patrick P La Vega-Talbott Maite M Labate Angelo A Lacey Austin A Lal Dennis D Laššuthová Petra P Lauxmann Stephan S Lawthom Charlotte C Leech Stephanie L SL Lehesjoki Anna-Elina AE Lemke Johannes R JR Lerche Holger H Lesca Gaetan G Leu Costin C Lewin Naomi N Lewis-Smith David D Li Gloria Hoi-Yee GH Liao Calwing C Licchetta Laura L Lin Chih-Hsiang CH Lin Kuang-Lin KL Linnankivi Tarja T Lo Warren W Lowenstein Daniel H DH Lowther Chelsea C Lubbers Laura L Lui Colin H T CHT Macedo-Souza Lucia Inês LI Madeleyn Rene R Madia Francesca F Magri Stefania S Maillard Louis L Marcuse Lara L Marques Paula P Marson Anthony G AG Matthews Abigail G AG May Patrick P Mayer Thomas T McArdle Wendy W McCarroll Steven M SM McGoldrick Patricia P McGraw Christopher M CM McIntosh Andrew A McQuillan Andrew A Meador Kimford J KJ Mei Davide D Michel Véronique V Millichap John J JJ Minardi Raffaella R Montomoli Martino M Mostacci Barbara B Muccioli Lorenzo L Muhle Hiltrud H Müller-Schlüter Karen K Najm Imad M IM Nasreddine Wassim W Neaves Samuel S Neubauer Bernd A BA Newton Charles R J C CRJC Noebels Jeffrey L JL Northstone Kate K Novod Sam S O'Brien Terence J TJ Owusu-Agyei Seth S Özkara Çiğdem Ç Palotie Aarno A Papacostas Savvas S SS Parrini Elena E Pato Carlos C Pato Michele M Pendziwiat Manuela M Pennell Page B PB Petrovski Slavé S Pickrell William O WO Pinsky Rebecca R Pinto Dalila D Pippucci Tommaso T Piras Fabrizio F Piras Federica F Poduri Annapurna A Pondrelli Federica F Posthuma Danielle D Powell Robert H W RHW Privitera Michael M Rademacher Annika A Ragona Francesca F Ramirez-Hamouz Byron B Rau Sarah S Raynes Hillary R HR Rees Mark I MI Regan Brigid M BM Reif Andreas A Reinthaler Eva E Rheims Sylvain S Ring Susan M SM Riva Antonella A Rojas Enrique E Rosenow Felix F Ryvlin Philippe P Saarela Anni A Sadleir Lynette G LG Salman Barış B Salmon Andrea A Salpietro Vincenzo V Sammarra Ilaria I Scala Marcello M Schachter Steven S Schaller André A Schankin Christoph J CJ Scheffer Ingrid E IE Schneider Natascha N Schubert-Bast Susanne S Schulze-Bonhage Andreas A Scudieri Paolo P Sedláčková Lucie L Shain Catherine C Sham Pak C PC Shiedley Beth R BR Siena S Anthony SA Sills Graeme J GJ Sisodiya Sanjay M SM Smoller Jordan W JW Solomonson Matthew M Spalletta Gianfranco G Sparks Kathryn R KR Sperling Michael R MR Stamberger Hannah H Steinhoff Bernhard J BJ Stephani Ulrich U Štěrbová Katalin K Stewart William C WC Stipa Carlotta C Striano Pasquale P Strzelczyk Adam A Surges Rainer R Suzuki Toshimitsu T Talarico Mariagrazia M Talkowski Michael E ME Taneja Randip S RS Tanteles George A GA Timonen Oskari O Timpson Nicholas John NJ Tinuper Paolo P Todaro Marian M Topaloglu Pınar P Tsai Meng-Han MH Tumiene Birute B Turkdogan Dilsad D Uğur-İşeri Sibel S Utkus Algirdas A Vaidiswaran Priya P Valton Luc L van Baalen Andreas A Vari Maria Stella MS Vetro Annalisa A Vlčková Markéta M von Brauchitsch Sophie S von Spiczak Sarah S Wagner Ryan G RG Watts Nick N Weber Yvonne G YG Weckhuysen Sarah S Widdess-Walsh Peter P Wiebe Samuel S Wolf Steven M SM Wolff Markus M Wolking Stefan S Wong Isaac I von Wrede Randi R Wu David D Yamakawa Kazuhiro K Yapıcı Zuhal Z Yis Uluc U Yolken Robert R Yücesan Emrah E Zagaglia Sara S Zahnert Felix F Zara Federico F Zimprich Fritz F Zizovic Milena M Zsurka Gábor G Neale Benjamin M BM Berkovic Samuel F SF

medRxiv : the preprint server for health sciences 20240920

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at ex ...[more]

PMID: 36865150

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Project description:ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113 genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p = 1.8 × 10-5 ), approaching study-wide significance in familial GGE (p = 3.0 × 10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9-7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3-6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3-2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9-1.9, FDR-adjusted p = .19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Dataset Information

Shared and distinct ultra-rare genetic risk for diverse epilepsies: A whole-exome sequencing study of 54,423 individuals across multiple genetic ancestries.

Publications

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

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