An integrated systems-level framework for deciphering multidrug resistant epilepsy.

用于破译多重耐药性癫痫的集成系统级框架。

• 批准号: MR/S02638X/1
• 负责人: Michael Johnson
• 金额: $ 109.1万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS02638X%2F1
• 关键词: integrated; systems; level; framework; deciphering

Epilepsy is a serious, common neurological disease - one in 26 people will develop epilepsy at some point in their life. Epilepsy has huge public health significance - it is the 5th most disabling disease in the World Health Organisation's rankings of disability by illness and accounts for 3% of all A&E attendances in the UK NHS alone. The greatest burden falls on the 20-30% of people with epilepsy who continue to have uncontrolled seizures despite all currently available antiepileptic drugs. These people are at a significantly increased risk of dying, as well as from other complications of their epilepsy such as memory and cognitive difficulties, and under and unemployment. Surprisingly, there has been no progress in improving seizure control in the last 50 years of anti-epileptic drug development, and none of the current antiepileptic drugs are disease modifying or curative. This absence of progress despite decades of research mandates a new scientific approach. Our project brings together three leading universities in the UK (Imperial College, University College London, Cambridge University) to combine data and expertise in order to address this major unmet clinical need. Our goal is ambitious - to find better drugs for treating epilepsy. Our project combines the largest and most comprehensive genetic datasets on drug response in epilepsy worldwide with proven "big-data" computational methods for working out how genes interact with each other to cause disease. Then, using the latest methods to connect disease mechanisms to drug targets, we aim to translate these insights to new therapies for people living with drug resistant epilepsy. Our project has the potential to transform the lives of people with drug resistant epilepsy, and to inform fundamental mechanisms of human brain function in health and disease generally.

癫痫是一种严重的，常见的神经系统疾病-每26人中就有一人会在一生中的某个时候患上癫痫。癫痫具有巨大的公共卫生意义-它是世界卫生组织疾病残疾排名中第五大致残性疾病，仅在英国NHS中就占所有A&E就诊人数的3%。最大的负担福尔斯在20-30%的癫痫患者身上，尽管有所有目前可用的抗癫痫药物，他们仍然有不受控制的癫痫发作。这些人死亡的风险显著增加，以及癫痫的其他并发症，如记忆和认知困难，以及失业和失业。令人惊讶的是，在过去50年的抗癫痫药物开发中，在改善癫痫发作控制方面没有进展，并且目前的抗癫痫药物都不是疾病修饰或治愈性的。尽管进行了数十年的研究，但仍缺乏进展，这就要求采取新的科学方法。我们的项目汇集了英国三所领先的大学（帝国理工学院、伦敦大学学院、剑桥大学），将联合收割机的数据和专业知识结合起来，以解决这一重大的未满足的临床需求。我们的目标是雄心勃勃的-找到更好的治疗癫痫的药物。我们的项目将全球最大和最全面的癫痫药物反应遗传数据集与经过验证的“大数据”计算方法相结合，用于研究基因如何相互作用导致疾病。然后，使用最新方法将疾病机制与药物靶点联系起来，我们的目标是将这些见解转化为针对耐药癫痫患者的新疗法。我们的项目有可能改变耐药性癫痫患者的生活，并为健康和疾病中人类大脑功能的基本机制提供信息。

项目成果

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

741,075 名个体中与癫痫发作相关的拷贝数变异的全基因组鉴定和表型特征。

• DOI: 10.1038/s41467-023-39539-6
• 发表时间: 2023-07-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Montanucci, Ludovica;Lewis-Smith, David;Collins, Ryan L.;Niestroj, Lisa-Marie;Parthasarathy, Shridhar;Xian, Julie;Ganesan, Shiva;Macnee, Marie;Bruenger, Tobias;Thomas, Rhys H.;Talkowski, Michael;Helbig, Ingo;Leu, Costin;Lal, Dennis;Motelow, Joshua E.;Povysil, Gundula;Dhindsa, Ryan S.;Stanley, Kate E.;Allen, Andrew S.;Goldstein, David B.;Feng, Yen-Chen Anne;Howrigan, Daniel P.;Abbott, Liam E.;Tashman, Katherine;Cerrato, Felecia;Cusick, Caroline;Singh, Tarjinder;Heyne, Henrike;Byrnes, Andrea E.;Churchhouse, Claire;Watts, Nick;Solomonson, Matthew;Lal, Dennis;Gupta, Namrata;Neale, Benjamin M.;Berkovic, Samuel F.;Lerche, Holger;Goldstein, David B.;Lowenstein, Daniel H.;Berkovic, Samuel F.;Lerche, Holger;Goldstein, David B.;Lowenstein, Daniel H.;Cavalleri, Gianpiero L.;Cossette, Patrick;Cotsapas, Chris;De Jonghe, Peter;Dixon-Salazar, Tracy;Guerrini, Renzo;Hakonarson, Hakon;Heinzen, Erin L.;Dhindsa, Ryan S.;Stanley, Kate E.;Helbig, Ingo;Kwan, Patrick;Marson, Anthony G.;Petrovski, Slave;Kamalakaran, Sitharthan;Sisodiya, Sanjay M.;Stewart, Randy;Weckhuysen, Sarah;Depondt, Chantal;Dlugos, Dennis J.;Scheffer, Ingrid E.;Striano, Pasquale;Freyer, Catharine;Krause, Roland;May, Patrick;McKenna, Kevin;Regan, Brigid M.;Bennett, Caitlin A.;Leech, Stephanie L.;Leu, Costin;Lewis-Smith, David;Berkovic, Samuel F.;Scheffer, Ingrid E.;Regan, Brigid M.;Bennett, Caitlin A.;Leech, Stephanie L.;O'Brien, Terence J.;Petrovski, Slave;Todaro, Marian;Kwan, Patrick;Weckhuysen, Sarah;De Jonghe, Peter;Stamberger, Hannah;Depondti, Chantal;Andrade, Danielle M.;Ali, Quratulain Zulfiqar;Sadoway, Tara R.;Krestel, Heinz;Schaller, Andre;Papacostas, Savvas S.;Kousiappa, Ioanna;Tanteles, George A.;Yiolanda, Christou;Sterbova, Katalin;Vlckova, Marketa;Sedlackova, Lucie;Lassuthova, Petra;Klein, Karl Martin;Rosenow, Felix;Reif, Philipp S.;Knake, Susanne;Neubauer, Bernd A.;Zimprich, Friedrich;Feucht, Martha;Reinthaler, Eva;Kunz, Wolfram S.;Zsurka, Gabor;Surges, Rainer;Baumgartner, Tobias H.;von Wrede, Randi;Helbig, Ingo;Klein, Karl Martin;Pendziwiat, Manuela;Muhle, Hiltrud;Rademacher, Annika;van Baalen, Andreas;von Spiczak, Sarah;Stephani, Ulrich;Afawi, Zaid;Korczyn, Amos D.;Kanaan, Moien;Canavati, Christina;Kurlemann, Gerhard;Mueller-Schlueter, Karen;Kluger, Gerhard;Haeusler, Martin;Blatt, Ilan;Lemke, Johannes R.;Krey, Ilona;Lerche, Holger;Weber, Yvonne G.;Wolking, Stefan;Becker, Felicitas;Lauxmann, Stephan;Bosselmann, Christian;Kegele, Josua;Hengsbach, Christian;Rau, Sarah;Steinhoff, Bernhard J.;Schulze-Bonhage, Andreas;Borggrafe, Ingo;Schankin, Christoph J.;Schubert-Bast, Susanne;Schreiber, Herbert;Mayer, Thomas;Korinthenberg, Rudolf;Brockmann, Knut;Wolff, Markus;Kurlemann, Gerhard;Dennig, Dieter;Madeleyn, Rene;Kegele, Josua;Kalviainen, Reetta;Saarela, Anni;Timonen, Oskari;Linnankivi, Tarja;Lehesjoki, Anna-Elina;Rheims, Sylvain;Lesca, Gaetan;Ryvlin, Philippe;Maillard, Louis;Valton, Luc;Derambure, Philippe;Bartolomei, Fabrice;Hirsch, Edouard;Michel, Veronique;Chassoux, Francine;Rees, Mark I.;Chung, Seo-Kyung;Pickrell, William O.;Powell, Robert H. W.;Baker, Mark D.;Fonferko-Shadrach, Beata;Lawthom, Charlotte;Anderson, Joe;Sisodiya, Sanjay M.;Schneider, Natascha;Balestrini, Simona;Zagaglia, Sara;Braatz, Vera;Marson, Anthony G.;Johnson, Michael R.;Auce, Pauls;Sills, Graeme J.;Kwan, Patrick;Baum, Larry W.;Sham, Pakc.;Cherny, Stacey S.;Lui, Colin H. T.;Cavalleri, Gianpiero L.;Delanty, Norman;Doherty, Colin P.;Shukralla, Arif;El-Naggar, Hany;Widdess-Walsh, Peter;Barisic, Nina;Canafoglia, Laura;Franceschetti, Silvana;Castellotti, Barbara;Granata, Tiziana;Ragona, Francesca;Striano, Pasquale;Zara, Federico;Iacomino, Michele;Riva, Antonella;Madia, Francesca;Vari, Maria Stella;Salpietro, Vincenzo;Scala, Marcello;Mancardi, Maria Margherita;Lino, Nobili;Amadori, Elisa;Giacomini, Thea;Bisulli, Francesca;Pippucci, Tommaso;Licchetta, Laura;Minardi, Raffaella;Tinuper, Paolo;Muccioli, Lorenzo;Mostacci, Barbara;Gambardella, Antonio;Labate, Angelo;Annesi, Grazia;Manna, Lorella;Gagliardi, Monica;Guerrini, Renzo;Parrini, Elena;Mei, Davide;Vetro, Annalisa;Bianchini, Claudia;Montomoli, Martino;Doccini, Viola;Barba, Carmen;Hirose, Shinichi;Ishii, Atsushi;Suzuki, Toshimitsu;Inoue, Yushi;Yamakawa, Kazuhiro;Beydoun, Ahmad;Nasreddine, Wassim;Khoueiry-Zgheib, Nathalie;Tumiene, Birute;Utkus, Algirdas;Sadleir, Lynette G.;King, Chontelle;Caglayan, S. Hande;Arslan, Mutluay;Yapici, Zuhal;Topaloglu, Pinar;Kara, Bulent;Yis, Uluc;Turkdogan, Dilsad;Gundogdu-Eken, Asli;Bebek, Nerses;Ugur-Iseri, Sibel;Baykan, Betul;Salman, Baris;Haryanyan, Garen;Yucesan, Emrah;Kesim, Yesim;Ozkara, Cigdem;Tsai, Meng-Han;Ho, Chen-Jui;Lin, Chih-Hsiang;Lin, Kuang-Lin;Chou, I-Jun;Poduri, Annapurna;Shiedley, Beth R.;Shain, Catherine;Noebels, Jeffrey L.;Goldman, Alicia;Busch, Robyn M.;Jehi, Lara;Najm, Imad M.;Lal, Dennis;Ferguson, Lisa;Khoury, Jean;Glauser, Tracy A.;Clark, Peggy O.;Buono, Russell J.;Ferraro, Thomas N.;Sperling, Michael R.;Dlugos, Dennis J.;Lo, Warren;Privitera, Michael;French, Jacqueline A.;Cossette, Patrick;Schachter, Steven;Hakonarson, Hakon;Lowenstein, Daniel H.;Kuzniecky, Ruben I.;Dlugos, Dennis J.;Devinsky, Orrin;Lowenstein, Daniel H.;Kuzniecky, Ruben I.;French, Jacqueline A.;Hegde, Manu;Greenberg, David A.;Helbig, Ingo;Ellis, Colin A.;Goldberg, Ethan;Helbig, Katherine L.;Lewis-Smith, David;Cosico, Mahgenn;Vaidiswaran, Priya;Fitch, Eryn;Newton, Charles R. J. C.;Kariuki, SymonM.;Wagner, Ryan G.;Owusu-Agyei, Seth;Cole, Andrew J.;McGraw, ChristopherM.;Siena, S. Anthony;Davis, Lea;Hucks, Donald;Faucon, Annika;Wu, David;Abou-Khalil, Bassel W.;Haas, Kevin;Taneja, Randip S.
• 通讯作者: Taneja, Randip S.

Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability.

• DOI: 10.1093/brain/awac296
• 发表时间: 2022-11-21
• 期刊: Brain : a journal of neurology

Single-cell Mendelian randomisation identifies cell-type specific genetic effects on human brain disease and behaviour

• DOI: 10.1101/2022.11.28.517913
• 发表时间: 2022-11
• 期刊: bioRxiv
• 作者: Alexander Haglund;V. Zuber;Yi-Fei Yang;Maya Abouzeid;Rahel Feleke;Jeong-Hun Ko;A. Nott;A. Babtie;J. D. Mills;L. Muhammed;L. Laaniste;D. Gveric;Daniel Clode;Susan Pagni;Ravishankara Bellampalli;Alyma Somani;K. McDade;J. Anink;L. Mesarosova;E. Aronica;M. Thom;S. Sisodiya;P. Srivastava;D. Malhotra;J. Bryois;L. Bottolo;Michael R. Johnson

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility.

• DOI: 10.1016/j.neuron.2021.12.034
• 发表时间: 2022-04-06
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Meijer, Mandy;Agirre, Eneritz;Kabbe, Mukund;van Tuijn, Cassandra A.;Heskol, Abeer;Zheng, Chao;Falcao, Ana Mendanha;Bartosovic, Marek;Kirby, Leslie;Calini, Daniela;Johnson, Michael R.;Corces, M. Ryan;Montine, Thomas J.;Chen, Xingqi;Chang, Howard Y.;Malhotra, Dheeraj;Castelo-Branco, Goncalo
• 通讯作者: Castelo-Branco, Goncalo

Distinct gene-set burden patterns underlie common generalized and focal epilepsies.

• DOI: 10.1016/j.ebiom.2021.103588
• 发表时间: 2021-10
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Koko M;Krause R;Sander T;Bobbili DR;Nothnagel M;May P;Lerche H;Epi25 Collaborative
• 通讯作者: Epi25 Collaborative