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Am J Hum Genet. 2019 Aug 1;105(2):267-282. doi: 10.1016/j.ajhg.2019.05.020. Epub 2019 Jul 18.

Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals.

Collaborators (241)

Feng YA, Howrigan DP, Abbott LE, Tashman K, Cerrato F, Singh T, Heyne H, Byrnes A, Churchhouse C, Watts N, Solomonson M, Lal D, Heinzen EL, Dhindsa RS, Stanley KE, Cavalleri GL, Hakonarson H, Helbig I, Krause R, May P, Weckhuysen S, Petrovski S, Kamalakaran S, Sisodiya SM, Cossette P, Cotsapas C, De Jonghe P, Dixon-Salazar T, Guerrini R, Kwan P, Marson AG, Stewart R, Depondt C, Dlugos DJ, Scheffer IE, Striano P, Freyer C, McKenna K, Regan BM, Bellows ST, Leu C, Bennett CA, Johns EMC, Macdonald A, Shilling H, Burgess R, Weckhuysen D, Bahlo M, O'Brien TJ, Todaro M, Stamberger H, Andrade DM, Sadoway TR, Mo K, Krestel H, Gallati S, Papacostas SS, Kousiappa I, Tanteles GA, Štěrbová K, Vlčková M, Sedláčková L, Laššuthová P, Klein KM, Rosenow F, Reif PS, Knake S, Kunz WS, Zsurka G, Elger CE, Bauer J, Rademacher M, Pendziwiat M, Muhle H, Rademacher A, van Baalen A, von Spiczak S, Stephani U, Afawi Z, Korczyn AD, Kanaan M, Canavati C, Kurlemann G, Müller-Schlüter K, Kluger G, Häusler M, Blatt I, Lemke JR, Krey I, Weber YG, Wolking S, Becker F, Hengsbach C, Rau S, Maisch AF, Steinhoff BJ, Schulze-Bonhage A, Schubert-Bast S, Schreiber H, Borggräfe I, Schankin CJ, Mayer T, Korinthenberg R, Brockmann K, Kurlemann G, Dennig D, Madeleyn R, Kälviäinen R, Auvinen P, Saarela A, Linnankivi T, Lehesjoki AE, Rees MI, Chung SK, Pickrell WO, Powell R, Schneider N, Balestrini S, Zagaglia S, Braatz V, Johnson MR, Auce P, Sills GJ, Baum LW, Sham PC, Cherny SS, Lui CHT, Barišić N, Delanty N, Doherty CP, Shukralla A, McCormack M, El-Naggar H, Canafoglia L, Franceschetti S, Castellotti B, Granata T, Zara F, Iacomino M, Madia F, Vari MS, Mancardi MM, Salpietro V, Bisulli F, Tinuper P, Licchetta L, Pippucci T, Stipa C, Minardi R, Gambardella A, Labate A, Annesi G, Manna L, Gagliardi M, Parrini E, Mei D, Vetro A, Bianchini C, Montomoli M, Doccini V, Marini C, Suzuki T, Inoue Y, Yamakawa K, Tumiene B, Sadleir LG, King C, Mountier E, Caglayan SH, Arslan M, Yapıcı Z, Yis U, Topaloglu P, Kara B, Turkdogan D, Gundogdu-Eken A, Bebek N, Uğur-İşeri S, Baykan B, Salman B, Haryanyan G, Yücesan E, Kesim Y, Özkara Ç, Poduri A, Shiedley BR, Shain C, Buono RJ, Ferraro TN, Sperling MR, Lo W, Privitera M, French JA, Schachter S, Kuzniecky RI, Devinsky O, Hegde M, Khankhanian P, Helbig KL, Ellis CA, Spalletta G, Piras F, Piras F, Gili T, Ciullo V, Reif A, McQuillin A, Bass N, McIntosh A, Blackwood D, Johnstone M, Palotie A, Pato MT, Pato CN, Bromet EJ, Carvalho CB, Achtyes ED, Azevedo MH, Kotov R, Lehrer DS, Malaspina D, Marder SR, Medeiros H, Morley CP, Perkins DO, Sobell JL, Buckley PF, Macciardi F, Rapaport MH, Knowles JA, Fanous AH, McCarroll SA, Gupta N, Gabriel SB, Daly MJ, Lander ES, Lowenstein DH, Goldstein DB, Lerche H, Berkovic SF, Neale BM.

Abstract

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), 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; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas 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 DEEs 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 lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

KEYWORDS:

burden analysis; epilepsy; epileptic encephalopathy; exome; seizures; sequencing

PMID:
31327507
DOI:
10.1016/j.ajhg.2019.05.020

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