[en] Previous studies suggested that severe epilepsies, e.g., developmental and epileptic encephalopathies (DEEs), are mainly caused by ultra-rare de novo genetic variants. For milder disease, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 control individuals. Here, we separately analyzed three different groups of epilepsies: severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in control individuals with an allele count R 1 and a minor allele frequency % 1:1,000, to be predicted as deleterious (CADD R 20), and to have an odds ratio in individuals with epilepsy R 2. We identified genes enriched with QRVs primarily in NAFE (n ¼ 72), followed by GGE (n ¼ 32) and DEE (n ¼ 21). This suggests that rare variants may play a more important role for causality of NAFE than for DEE. Moreover, we found that genes harboring QRVs, e.g., HSGP2, FLNA, or TNC, encode proteins that are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE that occur also in the general population, while in DEE and GGE, the contribution of such variants appears more limited.
Disciplines :
Neurology Genetics & genetic processes
Author, co-author :
Bundalian, Linnaeus
Su, Yin-Yuan
Chen, Siwei
Velluva, Akhil
Kirstein, Anna Sophia
Garten, Antje
Biskup, Saskia
Battke, Florian
Lal, Dennis
Heyne, Henrike O.
Platzer, Konrad
Lin, Chen-Ching
Lemke, Johannes R.
Duc, Diana Le
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
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Zack, M.M., Kobau, R., National and State Estimates of the Numbers of Adults and Children with Active Epilepsy — United States, 2015. MMWR Morb. Mortal. Wkly. Rep. 66 (2017), 821–825, 10.15585/mmwr.mm6631a1.
Chen, T., Giri, M., Xia, Z., Subedi, Y.N., Li, Y., Genetic and epigenetic mechanisms of epilepsy: A review. Neuropsychiatr. Dis. Treat. 13 (2017), 1841–1859, 10.2147/NDT.S142032.
Annegers, J.F., Hauser, W.A., Anderson, V.E., Kurland, L.T., The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology 32 (1982), 174–179, 10.1212/wnl.32.2.174.
Perucca, P., Bahlo, M., Berkovic, S.F., The Genetics of Epilepsy. Annu. Rev. Genomics Hum. Genet. 21 (2020), 205–230, 10.1146/annurev-genom-120219-074937.
Gracie, L., Rostami-Hochaghan, D., Taweel, B., Mirza, N., SAGAS Scientists' Collaborative. Ahmed, A., Al-Bahri, T., Alexander, M., Ali, L., Ashton, J., et al. The Seizure-Associated Genes Across Species (SAGAS) database offers insights into epilepsy genes, pathways and treatments. Epilepsia 63 (2022), 2403–2412, 10.1111/epi.17352.
Campbell, C., Leu, C., Feng, Y.C.A., Wolking, S., Moreau, C., Ellis, C., Ganesan, S., Martins, H., Oliver, K., Boothman, I., et al. The role of common genetic variation in presumed monogenic epilepsies. EBioMedicine, 81, 2022, 104098, 10.1016/j.ebiom.2022.104098.
Leu, C., Stevelink, R., Smith, A.W., Goleva, S.B., Kanai, M., Ferguson, L., Campbell, C., Kamatani, Y., Okada, Y., Sisodiya, S.M., et al. Polygenic burden in focal and generalized epilepsies. Brain 142 (2019), 3473–3481, 10.1093/brain/awz292.
International League Against Epilepsy Consortium on Complex Epilepsies Auce, P., Avbersek, A., Bahlo, M., Balding, D.J., Bast, T., Baum, L., Becker, A.J., Becker, F., Berghuis, B., et al. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun., 9, 2018, 5269, 10.1038/s41467-018-07524-z.
Epi4K consortium Epilepsy Phenome/Genome Project Berkovic, S.F., Bridgers, J., Burgess, R., Cavalleri, G., Chung, S.K., Cossette, P., Delanty, N., Dlugos, D., et al. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 16 (2017), 135–143, 10.1016/S1474-4422(16)30359-3.
Epi25 Collaborative Electronic address sberkovic@unimelbeduau Epi25 Collaborative Abbott, L.E., Tashman, K., Cerrato, F., Singh, T., Heyne, H., Byrnes, A., Churchhouse, C., Watts, N., et al. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals. Am. J. Hum. Genet. 105 (2019), 267–282, 10.1016/j.ajhg.2019.05.020.
Peljto, A.L., Barker-Cummings, C., Vasoli, V.M., Leibson, C.L., Hauser, W.A., Buchhalter, J.R., Ottman, R., Familial risk of epilepsy: A population-based study. Brain 137 (2014), 795–805, 10.1093/brain/awt368.
Hernandez, R.D., Uricchio, L.H., Hartman, K., Ye, C., Dahl, A., Zaitlen, N., Ultrarare variants drive substantial cis heritability of human gene expression. Nat. Genet. 51 (2019), 1349–1355, 10.1038/s41588-019-0487-7.
Manolio, T.A., Collins, F.S., Cox, N.J., Goldstein, D.B., Hindorff, L.A., Hunter, D.J., McCarthy, M.I., Ramos, E.M., Cardon, L.R., Chakravarti, A., et al. Finding the missing heritability of complex diseases. Nature 461 (2009), 747–753, 10.1038/nature08494.
Zuk, O., Schaffner, S.F., Samocha, K., Do, R., Hechter, E., Kathiresan, S., Daly, M.J., Neale, B.M., Sunyaev, S.R., Lander, E.S., Searching for missing heritability: Designing rare variant association studies. Proc. Natl. Acad. Sci. USA 111 (2014), E455–E464, 10.1073/pnas.1322563111.
Fu, J.M., Satterstrom, F.K., Peng, M., Brand, H., Collins, R.L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S.P., et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54 (2022), 1320–1331, 10.1038/s41588-022-01104-0.
Van der Auwera, G.A., O'Connor, B.D., Genomics in the Cloud: Using Docker, GATK, and WDL in Terra. 2020, O'Reilly Media.
McLaren, W., Gil, L., Hunt, S.E., Riat, H.S., Ritchie, G.R.S., Thormann, A., Flicek, P., Cunningham, F., The Ensembl Variant Effect Predictor. Genome Biol., 17, 2016, 122, 10.1186/s13059-016-0974-4.
Barry, W.T., Nobel, A.B., Wright, F.A., Significance analysis of functional categories in gene expression studies: A structured permutation approach. Bioinformatics 21 (2005), 1943–1949, 10.1093/bioinformatics/bti260.
Subramanian, A., Tamayo, P., Mootha, V.K., Mukherjee, S., Ebert, B.L., Gillette, M.A., Paulovich, A., Pomeroy, S.L., Golub, T.R., Lander, E.S., Mesirov, J.P., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102 (2005), 15545–15550, 10.1073/pnas.0506580102.
Kircher, M., Witten, D.M., Jain, P., O'roak, B.J., Cooper, G.M., Shendure, J., A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46 (2014), 310–315, 10.1038/ng.2892.
Miller, J.A., Ding, S.L., Sunkin, S.M., Smith, K.A., Ng, L., Szafer, A., Ebbert, A., Riley, Z.L., Royall, J.J., Aiona, K., et al. Transcriptional landscape of the prenatal human brain. Nature 508 (2014), 199–206, 10.1038/nature13185.
Hawrylycz, M.J., Lein, E.S., Guillozet-Bongaarts, A.L., Shen, E.H., Ng, L., Miller, J.A., Van De Lagemaat, L.N., Smith, K.A., Ebbert, A., Riley, Z.L., et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489 (2012), 391–399, 10.1038/nature11405.
Grote, S., Prüfer, K., Kelso, J., Dannemann, M., ABAEnrichment: An R package to test for gene set expression enrichment in the adult and developing human brain. Bioinformatics 32 (2016), 3201–3203, 10.1093/bioinformatics/btw392.
Liberzon, A., Subramanian, A., Pinchback, R., Thorvaldsdóttir, H., Tamayo, P., Mesirov, J.P., Molecular signatures database (MSigDB) 3.0. Bioinformatics 27 (2011), 1739–1740, 10.1093/bioinformatics/btr260.
Draghici, S., Khatri, P., Tarca, A.L., Amin, K., Done, A., Voichita, C., Georgescu, C., Romero, R., A systems biology approach for pathway level analysis. Genome Res. 17 (2007), 1537–1545, 10.1101/gr.6202607.
Wieder, C., Frainay, C., Poupin, N., Rodríguez-Mier, P., Vinson, F., Cooke, J., Lai, R.P., Bundy, J.G., Jourdan, F., Ebbels, T., Pathway analysis in metabolomics: Recommendations for the use of over-representation analysis. PLoS Comput. Biol., 17, 2021, e1009105, 10.1371/journal.pcbi.1009105.
Sjöstedt, E., Zhong, W., Fagerberg, L., Karlsson, M., Mitsios, N., Adori, C., Oksvold, P., Edfors, F., Limiszewska, A., Hikmet, F., et al. An atlas of the protein-coding genes in the human, pig, and mouse brain. Science, 367, 2020, eaay5947, 10.1126/SCIENCE.AAY5947.
Li, T., Wernersson, R., Hansen, R.B., Horn, H., Mercer, J., Slodkowicz, G., Workman, C.T., Rigina, O., Rapacki, K., Stærfeldt, H.H., et al. A scored human protein-protein interaction network to catalyze genomic interpretation. Nat. Methods 14 (2017), 61–64, 10.1038/nmeth.4083.
Oyrer, J., Maljevic, S., Scheffer, I.E., Berkovic, S.F., Petrou, S., Reid, C.A., Ion channels in genetic epilepsy: From genes and mechanisms to disease-targeted therapies. Pharmacol. Rev. 70 (2018), 142–173, 10.1124/pr.117.014456.
Reid, C.A., Berkovic, S.F., Petrou, S., Mechanisms of human inherited epilepsies. Prog. Neurobiol. 87 (2009), 41–57, 10.1016/j.pneurobio.2008.09.016.
Ge, S.X., Yao, R., Jung, D., Yao, R., ShinyGO: A graphical gene-set enrichment tool for animals and plants. Bioinformatics 36 (2020), 2628–2629, 10.1093/bioinformatics/btz931.
Penttilä, S., Palmio, J., Udd, B., ANO5-Related Muscle Diseases. 1993, University of Washington, Seattle.
Xu, J., El Refaey, M., Xu, L., Zhao, L., Gao, Y., Floyd, K., Karaze, T., Janssen, P.M.L., Han, R., Genetic disruption of Ano5 in mice does not recapitulate human ANO5-deficient muscular dystrophy. Skelet. Muscle, 5, 2015, 10.1186/s13395-015-0069-z 43–14.
Thiruvengadam, G., Sreetama, S.C., Charton, K., Hogarth, M., Novak, J.S., Suel-Petat, L., Chandra, G., Allard, B., Richard, I., Jaiswal, J.K., Anoctamin 5 Knockout Mouse Model Recapitulates LGMD2L Muscle Pathology and Offers Insight Into in vivo Functional Deficits. J. Neuromuscul. Dis. 8 (2021), S243–S255, 10.3233/JND-210720.
Qi, C., Feng, I., Costa, A.R., Pinto-Costa, R., Neil, J.E., Caluseriu, O., Li, D., Ganetzky, R.D., Brasch-Andersen, C., Fagerberg, C., et al. Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans. Genet. Med. 24 (2022), 319–331, 10.1016/j.gim.2021.09.014.
Focchi, E., Cambria, C., Pizzamiglio, L., Murru, L., Pelucchi, S., D'Andrea, L., Piazza, S., Mattioni, L., Passafaro, M., Marcello, E., et al. ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex. Cell Death Dis. 13 (2022), 616–713, 10.1038/s41419-022-05038-7.
Badouel, C., Zander, M.A., Liscio, N., Bagherie-Lachidan, M., Sopko, R., Coyaud, E., Raught, B., Miller, F.D., McNeill, H., Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development. Development (Camb.) 142 (2015), 2781–2791, 10.1242/dev.123539.
Endo, M., Doi, R., Nishita, M., Minami, Y., Ror family receptor tyrosine kinases regulate the maintenance of neural progenitor cells in the developing neocortex. J. Cell Sci. 125 (2012), 2017–2029, 10.1242/jcs.097782.
Iyengar, S.K., Elston, R.C., The Genetic Basis of Complex Traits. Methods in molecular biology, 2007, Methods Mol Biol, 71–84, 10.1007/978-1-59745-389-9_6.
Song, I., Dityatev, A., Crosstalk between glia, extracellular matrix and neurons. Brain Res. Bull. 136 (2018), 101–108, 10.1016/j.brainresbull.2017.03.003.
Dityatev, A., Fellin, T., Extracellular matrix in plasticity and epileptogenesis. Neuron Glia Biol. 4 (2008), 235–247, 10.1017/S1740925X09000118.
Dityatev, A., Remodeling of extracellular matrix and epileptogenesis. Epilepsia 51:Suppl 3 (2010), 61–65, 10.1111/j.1528-1167.2010.02612.x.
Wong, M., Degrading epilepsy: the role of extracellular proteases and the extracellular matrix. Epilepsy Curr. 12 (2012), 118–120, 10.5698/1535-7511-12.3.118.
Pitkänen, A., Ndode-Ekane, X.E., Łukasiuk, K., Wilczynski, G.M., Dityatev, A., Walker, M.C., Chabrol, E., Dedeurwaerdere, S., Vazquez, N., Powell, E.M., Neural ECM and epilepsy. Progress in Brain Research, 2014, Prog Brain Res, 229–262, 10.1016/B978-0-444-63486-3.00011-6.
McRae, P.A., Porter, B.E., The perineuronal net component of the extracellular matrix in plasticity and epilepsy. Neurochem. Int. 61 (2012), 963–972, 10.1016/j.neuint.2012.08.007.
Eskici, N.F., Erdem-Ozdamar, S., Dayangac-Erden, D., The altered expression of perineuronal net elements during neural differentiation. Cell. Mol. Biol. Lett., 23, 2018, 5, 10.1186/s11658-018-0073-5.
Devinsky, O., Vezzani, A., O'Brien, T.J., Jette, N., Scheffer, I.E., De Curtis, M., Perucca, P., Epilepsy. Nat. Rev. Dis. Primers, 4, 2018, 18024, 10.1038/nrdp.2018.24.
Heck, N., Garwood, J., Loeffler, J.P., Larmet, Y., Faissner, A., Differential upregulation of extracellular matrix molecules associated with the appearance of granule cell dispersion and mossy fiber sprouting during epileptogenesis in a murine model of temporal lobe epilepsy. Neuroscience 129 (2004), 309–324, 10.1016/j.neuroscience.2004.06.078.
Zai, C.C., Lee, F.H., Tiwari, A.K., Lu, J.Y., De Luca, V., Maes, M.S., Herbert, D., Shahmirian, A., Cheema, S.Y., Zai, G.C., et al. Investigation of the HSPG2Gene in tardive dyskinesia-new data and meta-analysis. Front. Pharmacol., 9, 2018, 974, 10.3389/fphar.2018.00974.
Trout, A.L., Kahle, M.P., Roberts, J.M., Marcelo, A., de Hoog, L., Boychuk, J.A., Grupke, S.L., Berretta, A., Gowing, E.K., Boychuk, C.R., et al. Perlecan Domain-V Enhances Neurogenic Brain Repair After Stroke in Mice. Transl. Stroke Res. 12 (2021), 72–86, 10.1007/s12975-020-00800-5.
Velluva, A., Radtke, M., Horn, S., Popp, B., Platzer, K., Gjermeni, E., Lin, C.-C., Lemke, J.R., Garten, A., Schöneberg, T., et al. Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies. BMC Genom., 22, 2021, 802, 10.1186/s12864-021-08125-9.
Heyes, S., Pratt, W.S., Rees, E., Dahimene, S., Ferron, L., Owen, M.J., Dolphin, A.C., Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog. Neurobiol. 134 (2015), 36–54, 10.1016/J.PNEUROBIO.2015.09.002.
Kambouris, M., Thevenon, J., Soldatos, A., Cox, A., Stephen, J., Ben-Omran, T., Al-Sarraj, Y., Boulos, H., Bone, W., Mullikin, J.C., et al. Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy. Ann. Clin. Transl. Neurol. 4 (2017), 26–35, 10.1002/acn3.372.
Shao, D., Baker, M.D., Abrahamsen, B., Rugiero, F., Malik-Hall, M., Poon, W.Y.L., Cheah, K.S.E., Yao, K.M., Wood, J.N., Okuse, K., A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel NaV1.8. Mol. Cell. Neurosci. 42 (2009), 219–225, 10.1016/j.mcn.2009.07.003.
Hiromoto, Y., Azuma, Y., Suzuki, Y., Hoshina, M., Uchiyama, Y., Mitsuhashi, S., Miyatake, S., Mizuguchi, T., Takata, A., Miyake, N., et al. Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia. Hum. Genome Var. 7 (2020), 43–45, 10.1038/s41439-020-00131-9.
Baldassarre, M., Razinia, Z., Brahme, N.N., Buccione, R., Calderwood, D.A., Filamin A controls matrix metalloproteinase activity and regulates cell invasion in human fibrosarcoma cells. J. Cell Sci. 125 (2012), 3858–3869, 10.1242/jcs.104018.
Chelyshev, Y.A., Kabdesh, I.M., Mukhamedshina, Y.O., Extracellular Matrix in Neural Plasticity and Regeneration. Cell. Mol. Neurobiol. 42 (2022), 647–664, 10.1007/s10571-020-00986-0.
Ferhat, L., Chevassus-Au-Louis, N., Khrestchatisky, M., Ben-Ari, Y., Represa, A., Seizures induce tenascin-C mRNA expression in neurons. J. Neurocytol. 25 (1996), 535–546, 10.1007/bf02284821.
International League Against Epilepsy Consortium on Complex Epilepsies Electronic address epilepsy-austin@unimelbeduau. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 13 (2014), 893–903, 10.1016/S1474-4422(14)70171-1.
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
