A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis
Rosella Mechelli, Renato Umeton, Gianmarco Bellucci, Riccardo Bigi, Virginia Rinaldi, Daniela F. Angelini, Gisella Guerrera, Francesca Chiara Pignalosa, Sara Ilari, Marco Patrone, Sundararajan Srinivasan, Gabriel Cerono, Silvia Romano, Maria Chiara Buscarinu, Serena Martire, Simona Malucchi, Doriana Landi, Lorena Lorefice, Raffaella Pizzolato Umeton, Eleni Anastasiadou, Pankaj Trivedi, Arianna Fornasiero, Michela Ferraldeschi, IMSGC WTCCC2, Alessia Di Sapio, Gerolama Alessandra Marfia, Eleonora Cocco, Diego Centonze, Antonio Uccelli, Dario Di Silvestre, Pierluigi Mauri, Paola de Candia, Sandra D’Alfonso, Luca Battistini, Cinthia Farina, Roberta Magliozzi, Richard Reynolds, Sergio E. Baranzini, Giuseppe Matarese, Marco Salvetti, Giovanni Ristori, Lars Alfredsson, Helle Bach Søndergaard, Sergio E. Baranzini, Lisa F. Barcellos, Luisa Bernardinelli, David Booth, Manuel Comabella, Alastair Compston, Chris Cotsapas, Sandra D’Alfonso, Efthimios Dardiotis, Philip L. De Jager, Bénédicte Dubois, Federica Esposito, B. Fontaine, An Goris, Pierre‐Antoine Gourraud, Giorgos M. Hadjigeorgiou, D A Hafler, Jonathan L. Haines, Hanne F. Harbo, Stephen L. Hauser, Bernhard Hemmer, Roland G. Henry, Hillert, Rogier Hintzen, Noriko Isobe, Adrian J. Ivinson, Seema Kalra, Michael Khalil, Ingrid Kockum, Jeanette Lechner-Scott, Roland Martinꝉ, Filippo Martinelli Boneschi, Jacob L. McCauley, Gil McVean, Jorge R. Oksenberg, Tomas Olsson, Annette Oturai, Grant P. Parnell, Nikolaos A. Patsopoulos, Margaret A. Pericak-Vance, Neil P. Robertson, Janna Saarela, Stephen Sawcer, Joost Smolders, G. J. Stewart, Bruce Taylor, V. Wee Yong, Frauke Zipp, Inês Barroso, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Mark J. Caulfield, David A. Clayton, Aiden Corvin, Nick Craddock
Abstract
Recent sero-epidemiological studies have strengthened the hypothesis that Epstein-Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV-host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.