Locus for severity implicates CNS resilience in progression of multiple sclerosis

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  • International Multiple Sclerosis Genetics Consortium
  • MultipleMS Consortium
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.
Sider (fra-til)323-331
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank all study participants for their support and for making this work possible. This work was supported by funding from the NIH/NINDS (R01NS099240) to S.E.B. and S.J.S., and the European Union’s Horizon 2020 Research and Innovation Funding Programme (EU RIA 733161) to MultipleMS. We acknowledge support from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. A.H. is supported by the NMSS-ABF Clinician Scientist Development Award (FAN-1808-32256) funded by the National Multiple Sclerosis Society (NMSS) and the Multiple Sclerosis Society of Canada (MSSC). We thank G. Liu for help with the longitudinal analyses. P.S. is supported by the Magretha af Ugglas foundation and Horizon 2020 EU grant (MultipleMS, 733161). S.E.B. holds the Professorship in Neurology I and the Heidrich Family and Friends Endowed Chair in Neurology. The UCSF DNA biorepository is supported by the NMSS (Si-2001-35701). J.L.M. acknowledges funding support from the NIH/NINDS (R01NS096212) and the Genentech Health Equity Innovation Fund (G-79758). L.A. has received academic grant support from the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare and the Swedish Brain foundation. S.R.D. has received institutional research grant funding from the NMSS and the NIH/NINDS. T.O. has received academic grant support from the Swedish Research Council, the Swedish Brain foundation, Knut and Alice Wallenberg foundation and Margaretha af Ugglas foundation. M.J.F.-P. has received grant support from the Multiple Sclerosis Society of Western Australia (MSWA). M.V. is a PhD fellow (11ZZZ21N) and B.D. is a Clinical Investigator of the Research Foundation Flanders (FWO-Vlaanderen). B.D. and A.G. have received academic grant support from the Research Fund KU Leuven (C24/16/045) and the Research Foundation Flanders (FWO G.07334.15). S.L. holds research support from the Spanish Government (PI21/010189, PI18/01030, PI15/00587), funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación and co-funded by the European Union, and the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0002, RD16/0015/0003). S.B. and F.Z. have received funding from the German Research Foundation (CRC-TR-128). F.Z. also acknowledges support from the Progressive MS Alliance (BRAVEinMS PA-1604-08492) and the Federal Ministry of Education and Research (VIP+ HaltMS-03VP07030). A.M. is supported by Margaretha af Ugglas foundation. B.H. is associated with DIFUTURE (Data Integration for Future Medicine) (BMBF 01ZZ1804[A-I]), and received funding for the study by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198]. The study was supported by the Italian Foundation of Multiple Sclerosis (FISM, 2011/R/14 2015/R/10, 2019/R-Multi/033, grants), Ricerca finalizzata, Italian Ministry of Health (RF-2016-02361294 grant), the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy. N.B. is partly supported by the MultipleMS project (Horizon 2020 European, grant 733161). N.A.P. was supported in part by the NMSS (grants JF-1808-32223 and RG-1707-28657). I. Kockum was partly supported by the MultipleMS project (Horizon 2020 European, Grant N. 733161), the Swedish Research Council (Grant N. 2020-01638), and the Swedish Brain foundation. L.F.B. is supported by the NIH (R01ES017080, R01AI076544, R01NS049510, and R01NR017431). We thank the late R. Q. Hintzen for his contributions to human genetic research.

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