{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:14:24Z","timestamp":1777612464885,"version":"3.51.4"},"reference-count":15,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Despite effective therapeutic control of relapses, many patients with multiple sclerosis (MS) experience, from the earliest phases of disease, disability accrual, which mostly occurs as progression independent of relapse activity (PIRA). In this observational study, we aimed at evaluating the genetic contribution to PIRA, using polygenic risk scores (PRS) in a cohort of 1162 Italian patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PRS were derived from the largest multi\u2010centric genome\u2010wide association study on MS severity, conducted on more than 20,000 patients. The scores were computed at 5 <jats:italic>p<\/jats:italic>\u2010value thresholds after a clumping procedure. Association with the rate of PIRA events was tested by fitting negative binomial regression models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analyses revealed a trend for association of PRS with the rate of PIRA events, which were significant in the subset of patients with age at onset \u2264\u200950\u2009years (Rate Ratio\u2009=\u20091.148, 95% CI: 1.01 to 1.304, <jats:italic>p<\/jats:italic>\u2009=\u20090.0328). An interaction effect was identified between PRS and AAO, indicating a significant mild antagonistic effect (RR<jats:sub>int<\/jats:sub>\u2009=\u20090.98, 95% CI: 0.96 to 1.0, <jats:italic>p<\/jats:italic>\u2009=\u20090.033).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest an influence of severity\u2010related genetic load on the rate of PIRA events, especially in subjects with disease onset before the age of 50\u2009years, characterized by a less prominent effect of aging processes on disability accumulation. This finding supports previous observations from other studies of an age\u2010dependent influence of genetic risk scores on complex traits.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.70264","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T07:54:27Z","timestamp":1751270067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Contribution of Polygenic Scores to Progression Independent of Relapse Activity in Multiple Sclerosis"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9561-4360","authenticated-orcid":false,"given":"Ferdinando","family":"Clarelli","sequence":"first","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology Laboratory of Human Genetics of Neurological Disorders  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4376-2550","authenticated-orcid":false,"given":"Melissa","family":"Sorosina","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology Laboratory of Human Genetics of Neurological Disorders  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-8311","authenticated-orcid":false,"given":"Antonino","family":"Giordano","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology Laboratory of Human Genetics of Neurological Disorders  Milan Italy"},{"name":"IRCCS Ospedale San Raffaele Neurology Unit and MS Center  Milan Italy"},{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele  Milan 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Institute of Experimental Neurology Laboratory of Human Genetics of Neurological Disorders  Milan Italy"},{"name":"IRCCS Ospedale San Raffaele Neurology Unit and MS Center  Milan Italy"},{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-4952","authenticated-orcid":false,"given":"Lucia","family":"Moiola","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale San Raffaele Neurology Unit and MS Center  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2358-4320","authenticated-orcid":false,"given":"Maria A.","family":"Rocca","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale San Raffaele Neurology Unit and MS Center  Milan Italy"},{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele  Milan Italy"},{"name":"IRCCS Ospedale San Raffaele, Division of Neuroscience Institute of Experimental 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