TY - JOUR
T1 - Locus for severity implicates CNS resilience in progression of multiple sclerosis
AU - International Multiple Sclerosis Genetics Consortium
AU - MultipleMS Consortium
AU - Harroud, Adil
AU - Stridh, Pernilla
AU - McCauley, Jacob L.
AU - Saarela, Janna
AU - van den Bosch, Aletta M.R.
AU - Engelenburg, Hendrik J.
AU - Beecham, Ashley H.
AU - Alfredsson, Lars
AU - Alikhani, Katayoun
AU - Amezcua, Lilyana
AU - Andlauer, Till F.M.
AU - Ban, Maria
AU - Barcellos, Lisa F.
AU - Barizzone, Nadia
AU - Berge, Tone
AU - Berthele, Achim
AU - Bittner, Stefan
AU - Bos, Steffan D.
AU - Briggs, Farren B.S.
AU - Caillier, Stacy J.
AU - Calabresi, Peter A.
AU - Caputo, Domenico
AU - Carmona-Burgos, David X.
AU - Cavalla, Paola
AU - Celius, Elisabeth G.
AU - Cerono, Gabriel
AU - Chinea, Angel R.
AU - Chitnis, Tanuja
AU - Clarelli, Ferdinando
AU - Comabella, Manuel
AU - Comi, Giancarlo
AU - Cotsapas, Chris
AU - Cree, Bruce C.A.
AU - D’Alfonso, Sandra
AU - Dardiotis, Efthimios
AU - De Jager, Philip L.
AU - Delgado, Silvia R.
AU - Dubois, Bénédicte
AU - Engel, Sinah
AU - Esposito, Federica
AU - Fabis-Pedrini, Marzena J.
AU - Filippi, Massimo
AU - Fitzgerald, Kathryn C.
AU - Gasperi, Christiane
AU - Gomez, Lissette
AU - Gomez, Refujia
AU - Hadjigeorgiou, Georgios
AU - Hamann, Jörg
AU - Held, Friederike
AU - Henry, Roland G.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2023.
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-023-06250-x
DO - 10.1038/s41586-023-06250-x
M3 - Article
C2 - 37380766
AN - SCOPUS:85164626113
SN - 0028-0836
VL - 619
SP - 323
EP - 331
JO - Nature
JF - Nature
IS - 7969
ER -