{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:02:11Z","timestamp":1793156531710,"version":"4.5.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-04741-7","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T16:23:52Z","timestamp":1751387032000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Aleksander","family":"Turk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ale\u0161","family":"Maver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Juvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Drulovi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0160arlota","family":"Mesaro\u0161","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Novakovi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada Star\u010devi\u0107","family":"\u010cizmarevi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smiljana","family":"Risti\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana Stankovi\u0107","family":"Mati\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borut","family":"Peterlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"4741_CR1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","volume":"4","author":"M Filippi","year":"2018","unstructured":"Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Primers. 4, 43 (2018).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"4741_CR2","first-page":"901","volume":"19","author":"BF Popescu","year":"2013","unstructured":"Popescu, B. F., Gh., Pirko, I. & Lucchinetti, C. F. Pathology of multiple sclerosis: where do we stand?? CONTINUUM: Lifelong Learn. Neurol. 19, 901\u2013921 (2013).","journal-title":"CONTINUUM: Lifelong Learn. Neurol."},{"key":"4741_CR3","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1177\/1352458513507625","volume":"19","author":"J Salzer","year":"2013","unstructured":"Salzer, J. & Myhr, K. M. Epstein\u2013Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: no. Mult Scler. 19, 1692\u20131693 (2013).","journal-title":"Mult Scler."},{"key":"4741_CR4","doi-asserted-by":"publisher","first-page":"eaav7188","DOI":"10.1126\/science.aav7188","volume":"365","author":"International Multiple Sclerosis Genetics Consortium","year":"2019","unstructured":"International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).","journal-title":"Science"},{"key":"4741_CR5","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/nrg3118","volume":"13","author":"G Gibson","year":"2012","unstructured":"Gibson, G. Rare and common variants: Twenty arguments. Nat. Rev. Genet. 13, 135\u2013145 (2012).","journal-title":"Nat. Rev. Genet."},{"key":"4741_CR6","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13073-015-0138-2","volume":"7","author":"PL Auer","year":"2015","unstructured":"Auer, P. L. & Lettre, G. Rare variant association studies: considerations, challenges and opportunities. Genome Med. 7, 16 (2015).","journal-title":"Genome Med."},{"key":"4741_CR7","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/ng.f.136","volume":"40","author":"W Bodmer","year":"2008","unstructured":"Bodmer, W. & Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nat. Genet. 40, 695\u2013701 (2008).","journal-title":"Nat. Genet."},{"key":"4741_CR8","doi-asserted-by":"publisher","first-page":"4065","DOI":"10.21037\/tcr-20-2395","volume":"9","author":"A Chattopadhyay","year":"2020","unstructured":"Chattopadhyay, A. & Lu, T. P. Overcoming the challenges of imputation of rare variants in a Taiwanese cohort. Transl Cancer Res. TCR. 9, 4065\u20134069 (2020).","journal-title":"Transl Cancer Res. TCR"},{"key":"4741_CR9","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/j.ajhg.2010.04.005","volume":"86","author":"AL Price","year":"2010","unstructured":"Price, A. L. et al. Pooled association tests for rare variants in Exon-Resequencing studies. Am. J. Hum. Genet. 86, 832\u2013838 (2010).","journal-title":"Am. J. Hum. Genet."},{"key":"4741_CR10","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1016\/j.cell.2018.09.049","volume":"175","author":"M Mitrovi\u010d","year":"2018","unstructured":"Mitrovi\u010d, M. et al. Low-Frequency and Rare-Coding variation contributes to multiple sclerosis risk. Cell 175, 1679\u20131687e7 (2018).","journal-title":"Cell"},{"key":"4741_CR11","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1034\/j.1399-0004.1999.560204.x","volume":"56","author":"A Sadovnick","year":"1999","unstructured":"Sadovnick, A., Dircks, A. & Ebers, G. Genetic counselling in multiple sclerosis: risks to Sibs and children of affected individuals: genetic counselling in MS. Clin. Genet. 56, 118\u2013122 (1999).","journal-title":"Clin. Genet."},{"key":"4741_CR12","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.neurol.2021.11.009","volume":"178","author":"A Balcerac","year":"2022","unstructured":"Balcerac, A. & Louapre, C. Genetics and Familial distribution of multiple sclerosis: A review. Rev. Neurol. 178, 512\u2013520 (2022).","journal-title":"Rev. Neurol."},{"key":"4741_CR13","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1111\/ane.13044","volume":"139","author":"M Steenhof","year":"2019","unstructured":"Steenhof, M. et al. Distribution of disease courses in Familial vs sporadic multiple sclerosis. Acta Neurol. Scand. 139, 231\u2013237 (2019).","journal-title":"Acta Neurol. Scand."},{"key":"4741_CR14","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1159\/000452256","volume":"81","author":"G Nicolas","year":"2016","unstructured":"Nicolas, G., Charbonnier, C. & Campion, D. From common to rare variants: the genetic component of alzheimer disease. Hum. Hered. 81, 129\u2013141 (2016).","journal-title":"Hum. Hered"},{"key":"4741_CR15","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41531-023-00608-8","volume":"10","author":"V Pitz","year":"2024","unstructured":"Pitz, V. et al. Analysis of rare parkinson\u2019s disease variants in millions of people. Npj Parkinsons Dis. 10, 11 (2024).","journal-title":"Npj Parkinsons Dis."},{"key":"4741_CR16","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1186\/s12864-024-10538-1","volume":"25","author":"TD Pottinger","year":"2024","unstructured":"Pottinger, T. D. et al. Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS. BMC Genom. 25, 651 (2024).","journal-title":"BMC Genom."},{"key":"4741_CR17","doi-asserted-by":"publisher","first-page":"e1008180","DOI":"10.1371\/journal.pgen.1008180","volume":"15","author":"C Vilari\u00f1o-G\u00fcell","year":"2019","unstructured":"Vilari\u00f1o-G\u00fcell, C. et al. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLoS Genet. 15, e1008180 (2019).","journal-title":"PLoS Genet."},{"key":"4741_CR18","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1002\/ana.22678","volume":"70","author":"SV Ramagopalan","year":"2011","unstructured":"Ramagopalan, S. V. et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann. Neurol. 70, 881\u2013886 (2011).","journal-title":"Ann. Neurol."},{"key":"4741_CR19","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","volume":"17","author":"AJ Thompson","year":"2018","unstructured":"Thompson, A. J. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17, 162\u2013173 (2018).","journal-title":"Lancet Neurol."},{"key":"4741_CR20","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The genome analysis toolkit: a mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297\u20131303 (2010).","journal-title":"Genome Res."},{"key":"4741_CR21","unstructured":"van der Auwera, G. & O\u2019Connor, B. D. Genomics in the Cloud: Using Docker, GATK, and WDL in Terra (O\u2019Reilly Media, 2020)."},{"key":"4741_CR22","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W. et al. The ensembl variant effect predictor. Genome Biol. 17, 122 (2016).","journal-title":"Genome Biol."},{"key":"4741_CR23","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434\u2013443 (2020).","journal-title":"Nature"},{"key":"4741_CR24","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","volume":"13","author":"P Rentzsch","year":"2021","unstructured":"Rentzsch, P., Schubach, M., Shendure, J. & Kircher, M. CADD-Splice\u2014improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med. 13, 31 (2021).","journal-title":"Genome Med."},{"key":"4741_CR25","doi-asserted-by":"publisher","unstructured":"Chen, S. et al. A Genome-Wide Mutational Constraint Map Quantified from Variation in 76,156 Human Genomes. https:\/\/doi.org\/10.1101\/2022.03.20.485034  (2022).","DOI":"10.1101\/2022.03.20.485034"},{"key":"4741_CR26","doi-asserted-by":"publisher","unstructured":"Clayton, D. snpStats: SnpMatrix and XSnpMatrix Classes and Methods. https:\/\/doi.org\/10.18129\/B9.bioc.snpStats  (2023).","DOI":"10.18129\/B9.bioc.snpStats"},{"key":"4741_CR27","unstructured":"Juvan, P., Maver, A., Majnik, T. & CMGgenomics CMGgenomics Workflows at KIGM\/CMG. Clinical Institute of Genomic Medicine (University Medical Centre Ljubljana, 2023)."},{"key":"4741_CR28","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2023)."},{"key":"4741_CR29","doi-asserted-by":"publisher","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","volume":"44","author":"NA O\u2019Leary","year":"2016","unstructured":"O\u2019Leary, N. A. et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 44, D733\u2013D745 (2016).","journal-title":"Nucleic Acids Res."},{"key":"4741_CR30","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.3389\/fimmu.2019.02067","volume":"10","author":"N Ugidos","year":"2019","unstructured":"Ugidos, N. et al. Interactome of the autoimmune risk protein ANKRD55. Front. Immunol. 10, 2067 (2019).","journal-title":"Front. Immunol."},{"key":"4741_CR31","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.isci.2018.03.010","volume":"2","author":"P Hofsteen","year":"2018","unstructured":"Hofsteen, P. et al. ALPK2 promotes cardiogenesis in zebrafish and human pluripotent stem cells. iScience 2, 88\u2013100 (2018).","journal-title":"iScience"},{"key":"4741_CR32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.molcel.2005.12.007","volume":"21","author":"Y Doyon","year":"2006","unstructured":"Doyon, Y. et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol. Cell. 21, 51\u201364 (2006).","journal-title":"Mol. Cell"},{"key":"4741_CR33","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.molcel.2014.06.006","volume":"55","author":"X Han","year":"2014","unstructured":"Han, X. et al. Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development. Mol. Cell. 55, 482\u2013494 (2014).","journal-title":"Mol. Cell"},{"key":"4741_CR34","doi-asserted-by":"publisher","first-page":"D933","DOI":"10.1093\/nar\/gkac958","volume":"51","author":"FJ Martin","year":"2023","unstructured":"Martin, F. J. et al. Ensembl 2023. Nucleic Acids Res. 51, D933\u2013D941 (2023).","journal-title":"Nucleic Acids Res."},{"key":"4741_CR35","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.3390\/cells10092465","volume":"10","author":"M Sobczak","year":"2021","unstructured":"Sobczak, M. et al. LSD1 facilitates Pro-Inflammatory polarization of macrophages by repressing catalase. Cells 10, 2465 (2021).","journal-title":"Cells"},{"key":"4741_CR36","doi-asserted-by":"publisher","first-page":"175628642110076","DOI":"10.1177\/17562864211007687","volume":"14","author":"S Haase","year":"2021","unstructured":"Haase, S. & Linker, R. A. Inflammation in multiple sclerosis. Ther. Adv. Neurol. Disord. 14, 175628642110076 (2021).","journal-title":"Ther. Adv. Neurol. Disord"},{"key":"4741_CR37","doi-asserted-by":"publisher","first-page":"e1006809","DOI":"10.1371\/journal.pgen.1006809","volume":"13","author":"R Oegema","year":"2017","unstructured":"Oegema, R. et al. Human mutations in integrator complex subunits link transcriptome integrity to brain development. PLoS Genet. 13, e1006809 (2017).","journal-title":"PLoS Genet."},{"key":"4741_CR38","doi-asserted-by":"crossref","unstructured":"Tong, H. et al. INTS8 accelerates the epithelial-to-mesenchymal transition in hepatocellular carcinoma by upregulating the TGF-\u03b2 signaling pathway. CMAR 11, 1869\u20131879 (2019).","DOI":"10.2147\/CMAR.S184392"},{"key":"4741_CR39","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.jneuroim.2010.10.028","volume":"230","author":"EM Meoli","year":"2011","unstructured":"Meoli, E. M., Oh, U., Grant, C. W. & Jacobson, S. TGF-\u03b2 signaling is altered in the peripheral blood of subjects with multiple sclerosis. J. Neuroimmunol. 230, 164\u2013168 (2011).","journal-title":"J. Neuroimmunol."},{"key":"4741_CR40","doi-asserted-by":"publisher","first-page":"5021","DOI":"10.21037\/tcr-24-110","volume":"13","author":"D Han","year":"2024","unstructured":"Han, D., Ling, B., Wu, C. & Jin, H. The role of IQCB1 in liver cancer: a bioinformatics analysis. Transl Cancer Res. 13, 5021\u20135036 (2024).","journal-title":"Transl Cancer Res."},{"key":"4741_CR41","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00018-015-2059-z","volume":"73","author":"M Jaworski","year":"2016","unstructured":"Jaworski, M. & Thome, M. The Paracaspase MALT1: biological function and potential for therapeutic Inhibition. Cell. Mol. Life Sci. 73, 459\u2013473 (2016).","journal-title":"Cell. Mol. Life Sci."},{"key":"4741_CR42","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1111\/febs.13325","volume":"282","author":"IS Afonina","year":"2015","unstructured":"Afonina, I. S., Elton, L., Carpentier, I. & Beyaert, R. MALT1 - a universal soldier: multiple strategies to ensure NF-\u03baB activation and target gene expression. FEBS J. 282, 3286\u20133297 (2015).","journal-title":"FEBS J."},{"key":"4741_CR43","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/1742-2094-11-124","volume":"11","author":"C Mc Guire","year":"2014","unstructured":"Mc Guire, C. et al. Pharmacological Inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis. J. Neuroinflamm. 11, 124 (2014).","journal-title":"J. Neuroinflamm."},{"key":"4741_CR44","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1111\/febs.16699","volume":"290","author":"I Skordos","year":"2023","unstructured":"Skordos, I. et al. Normal lymphocyte homeostasis and function in MALT1 protease-resistant HOIL \u20101 knock\u2010in mice. FEBS J. 290, 2032\u20132048 (2023).","journal-title":"FEBS J."},{"key":"4741_CR45","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jaci.2013.04.047","volume":"132","author":"HH Jabara","year":"2013","unstructured":"Jabara, H. H. et al. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J. Allergy Clin. Immunol. 132, 151\u2013158 (2013).","journal-title":"J. Allergy Clin. Immunol."},{"key":"4741_CR46","doi-asserted-by":"publisher","first-page":"16984","DOI":"10.1038\/s41598-022-21484-x","volume":"12","author":"E Everest","year":"2022","unstructured":"Everest, E. et al. Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation. Sci. Rep. 12, 16984 (2022).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-04741-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-04741-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-04741-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T16:23:54Z","timestamp":1751387034000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-04741-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4741"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-04741-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,1]]},"assertion":[{"value":"6 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee, the 1964 Helsinki Declaration and its later amendments or comparable ethical standards, the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine and the General Data Protection Regulation. Informed consent was obtained from all individual participants involved in the study. The study was approved by the Slovenian Committee for Medical Ethics (0120\u2009-66\/2024-2711-3).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"21200"}}