Harroud, Adil; Stridh, Pernilla J.; McCauley, Jacob H.; Saarela, Janna; van den Bosch, Aletta M. R.; Engelenburg, Hendrik; Beecham, Ashley; Alfredsson, Lars; Alikhani, Katayoun; Amezcua, Lilyana; Andlauer, Till F. M.; Ban, Maria; Barcellos, Lisa; Barizzone, Nadia; Berge, Tone; Berthele, Achim; Bittner, Stefan; Bos, Steffan; Briggs, Farren B. S.; Caillier, Stacy; Calabresi, Peter; Caputo, Domenico; Carmona-Burgos, David; Cavalla, Paola; Celius, Elisabeth; Cerono, Gabriel; Chinea, Angel; Chitnis, Tanuja; Clarelli, Ferdinando; Comabella, Manuel; Comi, Giancarlo; Cotsapas, Chris; Cree, Bruce C. A.; D'Alfonso, Sandra; Dardiotis, Efthimios; De Jager, Philip; Delgado, Silvia; Dubois, Benedicte; Engel, Sinah; Esposito, Federica; Fabis-Pedrini, Marzena; Filippi, Massimo; Fitzgerald, Kathryn; Gasperi, Christiane; Gomez, Lissette; Gomez, Refujia; Hadjigeorgiou, Georgios; Hamann, Joerg; Held, Friederike; Henry, Roland; Hillert, Jan; Huang, Jesse; Huitinga, Inge; Islam, Talat; Isobe, Noriko; Jagodic, Maja; Kermode, Allan L.; Khalil, Michael; Kilpatrick, Trevor; Konidari, Ioanna; Kreft, Karim; Lechner-Scott, Jeannette; Leone, Maurizio; Luessi, Felix; Malhotra, Sunny; Manouchehrinia, Ali; Manrique, Clara; Martinelli-Boneschi, Filippo; Martinez, Andrea; Martinez-Maldonado, Viviana; Mascia, Elisabetta; Metz, Luanne; Midaglia, Luciana; Montalban, Xavier; Oksenberg, Jorge; Olsson, Tomas; Oturai, Annette; Paakkonen, Kimmo; Parnell, Grant P.; Patsopoulos, Nikolaos; Pericak-Vance, Margaret; Piehl, Fredrik; Rubio, Justin; Santaniello, Adam; Santoro, Silvia; Schaefer, Catherine; Sellebjerg, Finn; Shams, Hengameh; Shchetynsky, Klementy; Silva, Claudia; Siokas, Vasileios; Sondergaard, Helle; Sorosina, Melissa; Taylor, Bruce; Vandebergh, Marijne; Vasileiou, Elena; Vecchio, Domizia; Voortman, Margarete; Weiner, Howard; Wever, Dennis; Yong, V. Wee; Hafler, David; Stewart, Graeme; Compston, Alastair; Zipp, Frauke; Harbo, Hanne; Hemmer, Bernhard; Goris, An; Smolders, Joost; Hauser, Stephen; Kockum, Ingrid; Sawcer, Stephen; Baranzini, Sergio; Jonsdottir, Ingileif; Blanco, Yolanda; Llufriu, Sara; Madireddy, Lohith; Saiz, Albert; Villoslada, Pablo; Stefansson, Kari; Harbo, Hanne F.; Hemmer, Bernhard; Goris, An; Kockum, Ingrid; Sawcer, Stephen J. und Baranzini, Sergio E.
(2023):
Locus for severity implicates CNS resilience in progression of multiple sclerosis.
In: Nature, Bd. 619, Nr. 7969: S. 329-331
[PDF, 3MB]
Abstract
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 adults(1,2). 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 susceptibility(3), these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.
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