{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:12:17Z","timestamp":1792843937383,"version":"4.5.0"},"reference-count":39,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mult Scler"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Observational studies suggest an association between immune responses to Epstein\u2013Barr virus nuclear antigen 1 (EBNA1) and multiple sclerosis (MS) risk. Nevertheless, a causal effect cannot be established, as confounding and reverse causation cannot be excluded.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We performed a bidirectional two-sample Mendelian randomization (MR) to test whether higher anti-EBNA1 IgG levels causally influence MS risk, or vice versa. Genetic associations for anti-EBNA1 IgG were obtained from 7972 UK Biobank participants, and for MS from 115,803 individuals in the International MS Genetics Consortium. Given that most anti-EBNA1 IgG instruments lie in the pleiotropic major histocompatibility complex, we applied a robust cis-MR framework, sensitivity analyses, and external validation using genetic association from anti-EBNA1 IgG levels obtained from 914 French individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      A one standard deviation increase in genetically predicted anti-EBNA1 IgG levels was causally associated with a 69% higher MS risk (OR = 1.69 [95% CI: 1.28; 2.23],\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      &lt; 0.001). Results were consistent across sensitivity analyses and showed no directional pleiotropy. External validation supported these findings. Reverse MR provided no evidence that MS influences anti-EBNA1 IgG levels (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      &gt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>These results support a unidirectional causal effect of elevated anti-EBNA1 IgG levels on MS risk, reinforcing the role of EBV-related immune responses in MS pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13524585261423063","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:39:34Z","timestamp":1773250774000},"page":"365-374","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["A bidirectional two-sample Mendelian randomization study of immune responses against Epstein\u2013Barr virus nuclear antigen 1 and multiple sclerosis in individuals of European ancestry"],"prefix":"10.1177","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7258-1938","authenticated-orcid":false,"given":"Andrea","family":"Nova","sequence":"first","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1913-9897","authenticated-orcid":false,"given":"Giovanni","family":"Di Caprio","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Gentilini","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"},{"name":"Bioinformatics and Statistical Genomic Unit, IRCCS Istituto Auxologico Italiano, Milan, 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