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Families with multiple cases of MS are rare but do occur. We hypothesised that multicase families may have a heightened polygenic risk for MS. In this work, we have determined whether polygenic risk for MS is enriched in multicase families in comparison to a case-control cohort. Using the findings from the largest MS genome-wide association study, we calculated a weighted polygenic risk score (wPRS) for MS. We applied this wPRS to study a population-based MS case-control cohort (3,252 people with MS and 5,725 controls) and three multicase MS families (9 individuals with MS, 10 unaffected family members). For both the population-based cohort and the three families, 167 of the 233 known genome-wide significant MS-associated variants were identified and used to calculate the wPRS. Within the population-based cohort, the wPRS was significantly higher in MS cases than controls (\n                    <jats:inline-formula>\n                      <a:math xmlns:a=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\">\n                        <a:mi>P<\/a:mi>\n                        <a:mo>=<\/a:mo>\n                        <a:mn>2.2<\/a:mn>\n                        <a:mo>\u00d7<\/a:mo>\n                        <a:msup>\n                          <a:mrow>\n                            <a:mn>10<\/a:mn>\n                          <\/a:mrow>\n                          <a:mrow>\n                            <a:mo>\u2212<\/a:mo>\n                            <a:mn>16<\/a:mn>\n                          <\/a:mrow>\n                        <\/a:msup>\n                      <\/a:math>\n                    <\/jats:inline-formula>\n                    ). The wPRS of familial MS cases was not significantly different to population-based MS cases (\n                    <jats:inline-formula>\n                      <c:math xmlns:c=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\">\n                        <c:mi>P<\/c:mi>\n                        <c:mo>&gt;<\/c:mo>\n                        <c:mn>0.05<\/c:mn>\n                      <\/c:math>\n                    <\/jats:inline-formula>\n                    ). Both affected and unaffected MS family members had higher wPRS than population controls. MS families have a higher polygenic risk for MS, but this did not differ to the polygenic risk of population-based MS cases. Only one family carried the established HLA-DRB1 15:01 MS risk allele, which was present in both affected and unaffected family members. Across families, unaffected family members had an elevated polygenic risk in comparison to population controls indicating that a higher polygenic risk does not fully explain the clustering of MS in families.\n                  <\/jats:p>","DOI":"10.1155\/2024\/9268911","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T21:35:06Z","timestamp":1715895306000},"page":"1-8","source":"Crossref","is-referenced-by-count":2,"title":["Multiple Sclerosis Polygenic Risk Is Not Enriched in Three Multicase Families in Comparison to Population-Based Cases"],"prefix":"10.1155","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0955-7601","authenticated-orcid":true,"given":"Ming","family":"Chen","sequence":"first","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"},{"name":"Department of Clinical Laboratory, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5552-2469","authenticated-orcid":true,"given":"Allan","family":"Motyer","sequence":"additional","affiliation":[{"name":"Melbourne Integrative Genomics, The University of Melbourne, Melbourne, Victoria, Australia"},{"name":"School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia"},{"name":"School of BioSciences, The University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-0070","authenticated-orcid":true,"given":"Bruce V.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1940-0007","authenticated-orcid":true,"given":"Bennet J.","family":"McComish","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-1249","authenticated-orcid":true,"given":"Kathryn P.","family":"Burdon","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6201-3518","authenticated-orcid":true,"given":"Jac C.","family":"Charlesworth","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-1539","authenticated-orcid":true,"given":"Nicholas B.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, 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