Journal Article

Locus for severity implicates CNS resilience in progression of multiple sclerosis

Berge, Tone, Hadjigeorgiou, Georgios, Parnell, Grant P., Leone, Maurizio, Kockum, Ingrid, Henry, Roland G., Manrique, Clara P., Andlauer, Till F. M., Islam, Talat, Mascia, Elisabetta, van den Bosch, Aletta M. R., Manouchehrinia, Ali, Esposito, Federica, Hafler, David A., Søndergaard, Helle B., Harbo, Hanne F., Ban, Maria, Chitnis, Tanuja, Gasperi, Christiane, Vecchio, Domizia, Smolders, Joost, Fabis-Pedrini, Marzena J., Chinea, Angel R., Kreft, Karim L., Montalban, Xavier, Stewart, Graeme J., Delgado, Silvia R., Compston, Alastair, Carmona-Burgos, David X., Hillert, Jan, Saarela, Janna, Vandebergh, Marijne, McCauley, Jacob L., Dubois, Bénédicte, Dardiotis, Efthimios, Santaniello, Adam, Beecham, Ashley H., Olsson, Tomas, Calabresi, Peter A., Yong, V. Wee, Madireddy, Lohith, Comabella, Manuel, Comi, Giancarlo, Isobe, Noriko, Khalil, Michael, Lechner-Scott, Jeannette, Santoro, Silvia, Clarelli, Ferdinando, Schaefer, Catherine, Barizzone, Nadia, Cotsapas, Chris, Rubio, Justin P., Barcellos, Lisa F., Huang, Jesse, Berthele, Achim, Caputo, Domenico, Goris, An, Piehl, Fredrik, Shchetynsky, Klementy, Celius,

2023

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 631/208/205/2138 / 631/250/38 / 631/378/371 / 692/699/375/1666 / Age / Aging / Autoimmune diseases / Brain - immunology / Brain - pathology / Brain - physiopathology / Brain stem / Brain Stem - immunology / Brain Stem - pathology / Brain Stem - physiopathology / Case-Control Studies / Central nervous system / Cognition / Cognitive Reserve / Confidence intervals / Disease Progression / Educational Status / Genome-wide association studies / Genome-Wide Association Study / Genomes / Heritability / Homozygote / Humanities and Social Sciences / Humans / Immunology / Mobility Limitation / multidisciplinary / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - immunology / Multiple Sclerosis - physiopathology / Multiple Sclerosis - psychology / Neurodegeneration / Neurological complications / Protective Factors / Quality control / Resilience / Science / Science (multidisciplinary) / Time Factors / Young Adult