Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.
Chen S., Abou-Khalil BW., Afawi Z., Ali QZ., Amadori E., Anderson A., Anderson J., Andrade DM., Annesi G., Arslan M., Auce P., Bahlo M., Baker MD., Balagura G., Balestrini S., Banks E., Barba C., Barboza K., Bartolomei F., Bass N., Baum LW., Baumgartner TH., Baykan B., Bebek N., Becker F., Bennett CA., Beydoun A., Bianchini C., Bisulli F., Blackwood D., Blatt I., Borggräfe I., Bosselmann C., Braatz V., Brand H., Brockmann K., Buono RJ., Busch RM., Caglayan SH., Canafoglia L., Canavati C., Castellotti B., Cavalleri GL., Cerrato F., Chassoux F., Cherian C., Cherny SS., Cheung C-L., Chou I-J., Chung S-K., Churchhouse C., Ciullo V., Clark PO., Cole AJ., Cosico M., Cossette P., Cotsapas C., Cusick C., Daly MJ., Davis LK., Jonghe PD., Delanty N., Dennig D., Depondt C., Derambure P., Devinsky O., Di Vito L., Dickerson F., Dlugos DJ., Doccini V., Doherty CP., El-Naggar H., Ellis CA., Epstein L., Evans M., Faucon A., Feng Y-CA., Ferguson L., Ferraro TN., Da Silva IF., Ferri L., Feucht M., Fields MC., Fitzgerald M., Fonferko-Shadrach B., Fortunato F., Franceschetti S., French JA., Freri E., Fu JM., Gabriel S., Gagliardi M., Gambardella A., Gauthier L., Giangregorio T., Gili T., Glauser TA., Goldberg E., Goldman A., Goldstein DB., Granata T., Grant R., Greenberg DA., Guerrini R., Gundogdu-Eken A., Gupta N., Haas K., Hakonarson H., Haryanyan G., Häusler M., Hegde M., Heinzen EL., Helbig I., Hengsbach C., Heyne H., Hirose S., Hirsch E., Ho C-J., Hoeper O., Howrigan DP., Hucks D., Hung P-C., Iacomino M., Inoue Y., Inuzuka LM., Ishii A., Jehi L., Johnson MR., Johnstone M., Kälviäinen R., Kanaan M., Kara B., Kariuki SM., Kegele J., Kesim Y., Khoueiry-Zgheib N., Khoury J., King C., Klein KM., Kluger G., Knake S., Kok F., Korczyn AD., Korinthenberg R., Koupparis A., Kousiappa I., Krause R., Krenn M., Krestel H., Krey I., Kunz WS., Kurlemann G., Kuzniecky RI., Kwan P., La Vega-Talbott M., Labate A., Lacey A., Lal D., Laššuthová P., Lauxmann S., Lawthom C., Leech SL., Lehesjoki A-E., Lemke JR., Lerche H., Lesca G., Leu C., Lewin N., Lewis-Smith D., Li GH-Y., Liao C., Licchetta L., Lin C-H., Lin K-L., Linnankivi T., Lo W., Lowenstein DH., Lowther C., Lubbers L., Lui CHT., Macedo-Souza LI., Madeleyn R., Madia F., Magri S., Maillard L., Marcuse L., Marques P., Marson AG., Matthews AG., May P., Mayer T., McArdle W., McCarroll SM., McGoldrick P., McGraw CM., McIntosh A., McQuillan A., Meador KJ., Mei D., Michel V., Millichap JJ., Minardi R., Montomoli M., Mostacci B., Muccioli L., Muhle H., Müller-Schlüter K., Najm IM., Nasreddine W., Neaves S., Neubauer BA., Newton CRJC., Noebels JL., Northstone K., Novod S., O'Brien TJ., Owusu-Agyei S., Özkara Ç., Palotie A., Papacostas SS., Parrini E., Pato C., Pato M., Pendziwiat M., Pennell PB., Petrovski S., Pickrell WO., Pinsky R., Pinto D., Pippucci T., Piras F., Piras F., Poduri A., Pondrelli F., Posthuma D., Powell RHW., Privitera M., Rademacher A., Ragona F., Ramirez-Hamouz B., Rau S., Raynes HR., Rees MI., Regan BM., Reif A., Reinthaler E., Rheims S., Ring SM., Riva A., Rojas E., Rosenow F., Ryvlin P., Saarela A., Sadleir LG., Salman B., Salmon A., Salpietro V., Sammarra I., Scala M., Schachter S., Schaller A., Schankin CJ., Scheffer IE., Schneider N., Schubert-Bast S., Schulze-Bonhage A., Scudieri P., Sedláčková L., Shain C., Sham PC., Shiedley BR., Siena SA., Sills GJ., Sisodiya SM., Smoller JW., Solomonson M., Spalletta G., Sparks KR., Sperling MR., Stamberger H., Steinhoff BJ., Stephani U., Štěrbová K., Stewart WC., Stipa C., Striano P., Strzelczyk A., Surges R., Suzuki T., Talarico M., Talkowski ME., Taneja RS., Tanteles GA., Timonen O., Timpson NJ., Tinuper P., Todaro M., Topaloglu P., Tsai M-H., Tumiene B., Turkdogan D., Uğur-İşeri S., Utkus A., Vaidiswaran P., Valton L., van Baalen A., Vari MS., Vetro A., Vlčková M., von Brauchitsch S., von Spiczak S., Wagner RG., Watts N., Weber YG., Weckhuysen S., Widdess-Walsh P., Wiebe S., Wolf SM., Wolff M., Wolking S., Wong I., von Wrede R., Wu D., Yamakawa K., Yapıcı Z., Yis U., Yolken R., Yücesan E., Zagaglia S., Zahnert F., Zara F., Zimprich F., Zizovic M., Zsurka G., Neale BM., Berkovic SF.
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 exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.