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We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune\u2010related genes in a Scandinavian case\u2013control cohort of 454 IIM patients and 1,024 healthy controls. Gene\u2010based aggregate testing, together with rare variant\u2013 and gene\u2010level enrichment analyses, was implemented to explore genotype\u2013phenotype relations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gene\u2010based aggregate tests of all variants, including rare variants, identified <jats:italic>IFI35<\/jats:italic> as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the <jats:italic>IFI35<\/jats:italic> locus highlighted a regulatory network linked to the skeletal muscle\u2013specific gene <jats:italic>PTGES3L<\/jats:italic>, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with <jats:italic>AGER<\/jats:italic> and <jats:italic>PSMB8<\/jats:italic> in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41929","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:31:56Z","timestamp":1626672716000},"page":"342-352","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3394-6495","authenticated-orcid":false,"given":"Matteo","family":"Bianchi","sequence":"first","affiliation":[{"name":"Science for Life Laboratory and Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6209-4100","authenticated-orcid":false,"given":"Sergey V.","family":"Kozyrev","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory and Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0272-2931","authenticated-orcid":false,"given":"Antonella","family":"Notarnicola","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Hultin Rosenberg","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory and Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c5sa","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory and Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-1373","authenticated-orcid":false,"given":"Pascal","family":"Pucholt","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2123-9902","authenticated-orcid":false,"given":"Simon","family":"Rothwell","sequence":"additional","affiliation":[{"name":"The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Alexsson","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-2321","authenticated-orcid":false,"given":"Johanna K.","family":"Sandling","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Andersson","sequence":"additional","affiliation":[{"name":"Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Aintree University Hospital MRC\u2010Arthritis Research UK Centre for integrated Research into Musculoskeletal Ageing, and University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2950-5670","authenticated-orcid":false,"given":"Leonid","family":"Padyukov","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tj\u00e4rnlund","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Dastmalchi","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The ImmunoArray Development Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The DISSECT Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0850-230X","authenticated-orcid":false,"given":"Jennifer R. 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