20.500.12556/DiRROS-24103 Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease affecting the central nervous system with many known genetic risk factors. Although genome-wide association studies (GWAS) have identified common genetic variants with small effects associated with MS, the role of rare variants with large effects in MS aetiology remains underexplored. We hypothesized that rare variants in MS-associated genes from GWAS studies (GWAS-associated genes) are more likely to contribute to familial MS (FMS) risk than to sporadic MS (SMS). Therefore, we aimed to assess the burden of rare, predicted pathogenic (RPP) variants in GWAS-associated genes in FMS and SMS patients compared to controls. Rare genetic variants in 111 GWAS-associated genes were assessed in 87 FMS, 89 SMS and 3866 control cases. We demonstrate that RPP variants were significantly overrepresented in the FMS cohort whereas their frequency was not increased in the SMS cohort compared to controls (p-values 5.27 × 10− 74 and 1.00, respectively). Six genes (ALPK2, ANKRD55, INTS8, IQCB1, JADE2, and MALT1) significantly contributed to the burden of RPP in the FMS group. We conclude that rare variants in genes identified by GWAS might contribute to the genetic predisposition of familial MS patients. multiple sclerosis burden analysis whole exome sequencing (WES) rare variants rare pathological changes candidate genes true false false Angleški jezik Ni določen Neznano 2025-11-12 12:09:44 2025-11-12 12:09:44 2025-11-13 08:30:55 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 9. 7. 2025; 6 str. article no. ǂ21200 Vol. 15 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 616.832-004 2045-2322 10.1038/s41598-025-04741-7 241991939 RAZ_Turk_Aleksander_2025.pdf RAZ_Turk_Aleksander_2025.pdf 1 D85EDF0FB041FAE8363DA3CF62846258 5f997f35955bd5a8239bf9900b7f45a64846335ab6ff0342eb65b9a19721659f 38cd3916-bfb8-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35851 https://www.nature.com/articles/s41598-025-04741-7 1 1aacbdd6-bfb8-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35850 Univerzitetni klinični center Ljubljana 0 0 0