Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Montanucci, L. et al. (2023) Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals. Nature Communications, 14(1), 4392. (doi: 10.1038/s41467-023-39539-6) (PMID:37474567) (PMCID:PMC10359300)

Abstract

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.

• Item Type: Articles
• Additional Information: This research was funded in whole, or in part, by the Wellcome Trust [203914/Z/16/Z], supporting D.L.S. I.H. was supported by The Hartwell Foundation (Individual Biomedical Research Award), the National Institute for Neurological Disorders and Stroke (K02 NS112600), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children’s Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984), and by the German Research Foundation (HE5415/3-1, HE5415/5-1, HE5415/6-1, HE5415/7-1). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878), by the Institute for Translational Medicine and Therapeutics’ (ITMAT) at the Perelman School of Medicine of the University of Pennsylvania, and by Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). R.L.C. was supported by NHGRI T32HG002295 and NSF GRFP #2017240332. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: Montanucci, L., Lewis-Smith, D., Collins, R. L., Niestroj, L.-M., Parthasarathy, S., Xian, J., Ganesan, S., Macnee, M., Brünger, T., Thomas, R. H., Talkowski, M., Motelow, J. E., Povysil, G., Dhindsa, R. S., Stanley, K. E., Allen, A. S., Goldstein, D. B., Feng, Y.-C. A., Howrigan, D. P., Abbott, L. E., Tashman, K., Cerrato, F., Cusick, C., Singh, T., Heyne, H., Byrnes, A. E., Churchhouse, C., Watts, N., Solomonson, M., Lal, D., Gupta, N., Neale, B. M., Berkovic, S. F., Lerche, H., Lowenstein, D. H., Cavalleri, G. L., Cossette, P., Cotsapas, C., De Jonghe, P., Dixon-Salazar, T., Guerrini, R., Hakonarson, H., Heinzen, E. L., Helbig, I., Kwan, P., Marson, A. G., Petrovski, S., Kamalakaran, S., Sisodiya, S. M., Stewart, R., Weckhuysen, S., Depondt, C., Dlugos, D. J., Scheffer, I. E., Striano, P., Freyer, C., Krause, R., May, P., McKenna, K., Regan, B. M., Bennett, C. A., Leech, S. L., Leu, C., Lewis-Smith, D., O’Brien, T. J., Todaro, M., Stamberger, H., Depondti, C., Andrade, D. M., Ali, Q. Z., Sadoway, T. R., Krestel, H., Schaller, A., Papacostas, S. S., Kousiappa, I., Tanteles, G. A., Yiolanda, C., Štěrbová, K., Vlčková, M., Sedláčková, L., Laššuthová, P., Klein, K. M., Rosenow, F., Reif, P. S., Knake, S., Neubauer, B. A., Zimprich, F., Feucht, M., Reinthaler, E., Kunz, W. S., Zsurka, G., Surges, R., Baumgartner, T. H., von Wrede, R., Helbig, I., Pendziwiat, M., Muhle, H., Rademacher, A., van Baalen, A., von Spiczak, S., Stephani, U., Afawi, Z., Korczyn, A. D., Kanaan, M., Canavati, C., Kurlemann, G., Müller-Schlüter, K., Kluger, G., Häusler, M., Blatt, I., Lemke, J. R., Krey, I., Weber, Y. G., Wolking, S., Becker, F., Lauxmann, S., Bosselmann, C., Kegele, J., Hengsbach, C., Rau, S., Steinhoff, B. J., Schulze-Bonhage, A., Borggräfe, I., Schankin, C. J., Schubert-Bast, S., Schreiber, H., Mayer, T., Korinthenberg, R., Brockmann, K., Wolff, M., Kurlemann, G., Dennig, D., Madeleyn, R., Kälviäinen, R., Saarela, A., Timonen, O., Linnankivi, T., Lehesjoki, A.-E., Rheims, S., Lesca, G., Ryvlin, P., Maillard, L., Valton, L., Derambure, P., Bartolomei, F., Hirsch, E., Michel, V., Chassoux, F., Rees, M. I., Chung, S.-K., Pickrell, W. O., Powell, R. H. W., Baker, M. D., Fonferko-Shadrach, B., Lawthom, C., Anderson, J., Schneider, N., Balestrini, S., Zagaglia, S., Braatz, V., Johnson, M. R., Auce, P., Sills, G. J., Kwan, P., Baum, L. W., Sham, P. C., Cherny, S. S., Lui, C. H. T., Delanty, N., Doherty, C. P., Shukralla, A., El-Naggar, H., Widdess-Walsh, P., Barišić, N., Canafoglia, L., Franceschetti, S., Castellotti, B., Granata, T., Ragona, F., Zara, F., Iacomino, M., Riva, A., Madia, F., Vari, M. S., Salpietro, V., Scala, M., Mancardi, M. M., Lino, N., Amadori, E., Giacomini, T., Bisulli, F., Pippucci, T., Licchetta, L., Minardi, R., Tinuper, P., Muccioli, L., Mostacci, B., Gambardella, A., Labate, A., Annesi, G., Manna, L., Gagliardi, M., Parrini, E., Mei, D., Vetro, A., Bianchini, C., Montomoli, M., Doccini, V., Barba, C., Hirose, S., Ishii, A., Suzuki, T., Inoue, Y., Yamakawa, K., Beydoun, A., Nasreddine, W., Khoueiry-Zgheib, N., Tumiene, B., Utkus, A., Sadleir, L. G., King, C., Caglayan, S. H., Arslan, M., Yapıcı, Z., Topaloglu, P., Kara, B., Yis, U., Turkdogan, D., Gundogdu-Eken, A., Bebek, N., Uğur-İşeri, S., Baykan, B., Salman, B., Haryanyan, G., Yücesan, E., Kesim, Y., Özkara, Ç., Tsai, M.-H., Ho, C.-J., Lin, C.-H., Lin, K.-L., Chou, I.-J., Poduri, A., Shiedley, B. R., Shain, C., Noebels, J. L., Goldman, A., Busch, R. M., Jehi, L., Najm, I. M., Lal, D., Ferguson, L., Khoury, J., Glauser, T. A., Clark, P. O., Buono, R. J., Ferraro, T. N., Sperling, M. R., Dlugos, D. J., Lo, W., Privitera, M., French, J. A., Schachter, S., Kuzniecky, R. I., Devinsky, O., Hegde, M., Greenberg, D. A., Ellis, C. A., Goldberg, E., Helbig, K. L., Cosico, M., Vaidiswaran, P., Fitch, E., Newton, C. R. J. C., Kariuki, S. M., Wagner, R. G., Owusu-Agyei, S., Cole, A. J., McGraw, C. M., Siena, S. A., Davis, L., Hucks, D., Faucon, A., Wu, D., Abou-Khalil, B. W., Haas, K., Taneja, R. S., Helbig, I., Leu, C., and Lal, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Published Online: 20 July 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature Communications 14(1):4392
• Publisher Policy: Reproduced under a Creative Commons License