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Locus for severity implicates CNS resilience in progression of multiple sclerosis

2023; Nature Portfolio; Volume: 619; Issue: 7969 Linguagem: Inglês

10.1038/s41586-023-06250-x

1476-4687

Adil Harroud, Pernilla Stridh, Jacob L. McCauley, Janna Saarela, Aletta M.R. van den Bosch, Hendrik J. Engelenburg, Ashley Beecham, Lars Alfredsson, Katayoun Alikhani, Lilyana Amezcua, Till F. M. Andlauer, Maria Ban, Lisa F. Barcellos, Nadia Barizzone, Tone Berge, Achim Berthele, Stefan Bittner, Steffan D. Bos, Farren Briggs, Stacy J. Caillier, Peter A. Calabresi, Domenico Caputo, David X. Carmona-Burgos, Paola Cavalla, Elisabeth Gulowsen Celius, Gabriel Cerono, Ángel Chinea, Tanuja Chitnis, Ferdinando Clarelli, Manuel Comabella, Gıancarlo Comı, Chris Cotsapas, Bruce Cree, Sandra D’Alfonso, Efthimios Dardiotis, Philip L. De Jager, Silvia Delgado, Bénédicte Dubois, Sinah Engel, Federica Esposito, Marzena J. Fabis‐Pedrini, Massimo Filippi, Kathryn C. Fitzgerald, Christiane Gasperi, Lissette Gomez, Refujia Gomez, Georgios M. Hadjigeorgiou, Jörg Hamann, Friederike Held, Roland G. Henry, Jan Hillert, Jesse Huang, Inge Huitinga, Talat Islam, Noriko Isobe, Maja Jagodic, Allan G. Kermode, Michael Khalil, Trevor J. Kilpatrick, Ioanna Konidari, Karim L. Kreft, Jeannette Lechner‐Scott, Maurizio Leone, Felix Luessi, Sunny Malhotra, Ali Manouchehrinia, Clara P. Manrique, Filippo Martinelli Boneschi, Andrea C. Martinez, Viviana Martínez-Maldonado, Elisabetta Mascia, Luanne M. Metz, Luciana Midaglia, Xavier Montalbán, Jorge R. Oksenberg, Tomas Olsson, Annette Oturai, Kimmo Pääkkönen, Grant P. Parnell, Nikolaos A. Patsopoulos, Margaret A. Pericak‐Vance, Fredrik Piehl, Justin P. Rubio, Adam Santaniello, Silvia Santoro, Catherine Schaefer, Finn Sellebjerg, Hengameh Shams, Klementy Shchetynsky, Cláudia Silva, Vasileios Siokas, Helle Bach Søndergaard, Melissa Sorosina, Bruce Taylor, Marijne Vandebergh, Eleni S. Vasileiou, Domizia Vecchio, Margarete M. Voortman, Howard L. Weiner, Dennis Wever, V. Wee Yong, David A. Hafler, Graeme J. Stewart, Alastair Compston, Frauke Zipp, Hanne F. Harbo, Bernhard Hemmer, An Goris, Joost Smolders, Stephen L. Hauser, Ingrid Kockum, Stephen Sawcer, Sergio E. Baranzini, Adil Harroud, Ingileif Jónsdóttir, Yolanda Blanco, Sara Llufriú, Lohith Madireddy, Albert Saiz, Pablo Villoslada, Kári Stéfansson,

Systemic Lupus Erythematosus Research

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3–PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS. A genome-wide association study including 22,389 cases of multiple sclerosis finds an association with disease progression at the DYSF–ZNF638 and DNM3–PIGC loci and identifies a potential of higher educational attainment in slowing disease progression.